All patients with suspected NSOI require a full ophthalmic assessment/workup.

NSOI is
typically characterized by the abrupt onset of pain, proptosis and other inflammatory signs such
as swelling and erythema. Unilateral presentation is more typical but bilateral presentations are
not uncommon.[23] Pediatric NSOI differs from the adult presentation and is more commonly
characterized by bilateral manifestation, uveitis, disc edema and eosinophilia.[24] Pain is the most
common symptom in adult NSOI and occurs 58-69% of the time followed by diplopia (31-
38%).[24][25] Periorbital edema/swelling is the most common sign and occurs 75-79.2% of the
time (figure) followed by proptosis (32-62.5%), EOM restriction (54.2%) red eye (48%),
chemosis (29%), decreased vision (20.8%), and ptosis (16.7%).34-35 Therefore, physical
examination of patients with suspected NSOI involves lid assessment (retraction/lid
lag/lagophthalmos), orbital assessment (proptosis), extraocular muscles (restriction), globe
(injection/chemosis), and optic nerve function (visual acuity/color plates/relative afferent
pupillary defect). Because of the association between rheumatologic disease and NSOI the
typical laboratory work-up for suspected NSOI should include a complete blood count, basic
metabolic panel, thyroid function studies, erythrocyte sedimentation rate, antinuclear antibodies,
antineutrophil cytoplasmic antibodies, angiotensin-converting enzyme level, rapid plasma reagin
test, and rheumatoid factor.[8]

Figure 1: Dense upper eyelid edema and swelling in a patient with lacrimal gland NSOI, Courtesy of
Professor M Chua

Imaging
Evaluation of NSOI will frequently involve high-resolution computed tomography (CT) or
contrast-enhanced magnetic resonance imaging (MRI). CT is the preferred method because of its
good inherent contrast of orbital fat, muscle, bony structures, and air in the adjacent paranasal
sinuses.[2] MRI is preferred in demonstrating soft tissue changes in the region of the cavernous
sinus/superior orbital fissure due to beam hardening and bone streak artifacts seen in CT.[26]
Kapur et al.[27] have noted different intensities diffusion-weighted imaging (DWI) between
NSOI, orbital cellulitis and orbital lymphoid. Therefore, DWI may help differentiate these
entities.[27] Radiologic findings allow subtypes of NSOI to be more precisely classified and are as
follows:[1][25][28][29][30][31]

Lacrimal gland

The lacrimal gland will appear diffusely enlarged with overall preservation of its shape. There
may be blurring at the gland margin with marked expansion along the lateral orbital wall and
lateral rectus muscle (Figure 2).

Figure 2: Diffusely enlarged right lacrimal gland with blurring of gland margin. Courtesy of
Professor M Chua

Extraocular muscles

Enlargement of the extraocular muscles will be seen (single or multiple). Unilateral single
muscle inflammation with tendon involvement is most common. The most frequently involved
muscle is the medial rectus followed by the superior rectus, lateral rectus and inferior rectus. The
tendon may also enlarge and together with enlargement of the muscle bundle lead to a tubular
configuration (Figure 3). There may be infiltrates throughout the orbital fat bordering the muscle,
blurring the margin of the muscle.
Figure 3: CT image of bilateral medial and lateral rectus tubular-like enlargement with tendon
involvement. Courtesy of Z.X. Ding

Optic nerve

Inflammatory tissues surrounding an unenhanced optic nerve may demonstrate the classical,
"tramline" sign (Figure 4). There may be streaky densities in the contiguous orbital fat.

Figure 4: CT image of optic nerve involvement with sheath enhancement ("tramline" sign) (asterisks),
white arrow showing right lacrimal gland enlargement. Courtesy of Z.X. Ding
Sclera, episclera, Tenon's capsule, and uvea:

Imaging will demonstrate non-specific thickening of structures. Blurring of the sclera margin may be
seen (Figure 5).

Figure 5: CT image showing thickening and blurring of left eye uveoscleral (asterisks). Courtesy
of Z.X. Ding

Orbital fat

Diffuse infiltration and inflammation will be seen in the orbital fat and may envelop the globe
and optic nerve sheath complex (Figure 6).

Figure 6: CT image showing enhancement of orbital fat (asterisks). Courtesy of Z.X. Ding

Orbital apex, cavernous sinus and intracranial involvement:

There may be compression, obliteration or displacement of the optic nerve. The cavernous sinus
(Figure 7) and middle cranial fossa are the two most common locations for intracranial extension
of NSOI. Intracranial involvement can feature abnormal soft tissue in the superior orbital fissure,
expansion of the ipsilateral cavernous sinus and thickening of the meninges contiguous with the
orbital inflammation.

Figure 7: MRI, fat-saturated, T1-weighted image with white arrows showing extension into the
cavernous sinus. Courtesy of Z.X. Ding

Biopsy

Biopsy for NSOI is not usually indicated. There may be not be a distinct mass to biopsy or the
lesion may be unapproachable and response to therapy can be confirmatory.[32] Biopsy may be
considered if there are progressive neurologic deficits, lack of steroid responsiveness and
persistent imaging abnormalities.
Figure 8: Showing whitish infiltration of the lacrimal gland on direct upper eyelid incision, Courtesy of
Professor M Chua

Differential Diagnosis

There are many processes that can mimic NSOI. The most common orbital processes that present
with similar clinical pictures as NSOI are thyroid eye disease and orbital cellulitis.9 Thyroid eye
disease is the most common cause of orbital inflammation in adults and has been found to
account for nearly 60% of cases of orbital inflammation in the 21-60 year old age group.[33]
Orbital cellulitis risk factors include history of sinusitis, dental work/disease, or trauma.[34][35]
Table 1 outlines common differential diagnosis for NSOI.

Table 1: Differential Diagnosis of Orbital Inflammation[8][25][32][35][36][37][38][39][40][41][42]

Management
Observation
Observation for NSOI for mild cases of inflammation may be acceptable. Swamy et al.[7]
reviewed the treatment of 24 NSOI patients with a minimum 6 month follow-up and found that
20.8% (5/24) that were treated with observation alone had maintained remission. If there is no
clinical resolution or worsening of symptoms then additional therapy is indicated.

Non-steroidal anti-inflammatory drugs (NSAIDs)

NSAIDs, such as ibuprofen, have been used in mild cases of NSOI. There has been no formal
study evaluating the use of NSAIDS in NSOI. Mannor et al.[43] reported that NSAIDs could be
used up to 3 weeks as long as clinical resolution was being observed, with steroids reserved for
refractory cases. The side effects to NSAIDs are dose-dependent with an estimated 10-20% of
NSAID patients experiencing dyspepsia which can be reduced through suppressing acid
production, via a proton pump inhibitor, e.g. omeprazole or esomeprazole.[44]

Corticosteroids

Systemic corticosteroids are generally considered mainstay therapy for NSOI.[8][32] Typically,
response to steroids is rapid with a dramatic improvement in all symptoms and findings. In their
review of 65 NSOI patients, Yuen and Ruben[23] found that 69% were treated with steroids alone,
12% with steroids and radiation therapy and 9% with steroids and NSAIDs. Yuen and Ruben[23]
also noted that 24 patients had treatment failures with steroid dependence and steroid intolerance
occurring 33% and 13% of the time, respectively. Idiopathic sclerosing inflammation of the
orbit: a distinct clinicopathological entity. Ophthalmology 1994;101:570-584</ref>[45] Treatment
doses can differ in range but are generally 1.0-1.5 mg/kg or 50-100 mg/day for 1-2 weeks
followed by slow taper for 5-8 weeks.

Radiation therapy

Radiation therapy can be used in the treatment of NSOI. It is generally used when NSOI is found
to be resistant to or intolerant to corticosteroid therapy.[46] The results of radiotherapy have been
reported to have success rates ranging between 50-75%.[47][48] Other authors have published
greater long-term control to ranging from 66%-100% success after a total dosage of 2000
cGy.[47][49] In there review of 24 NSOI patients treated with radiation therapy, Lanciano et al.[47]
found that 87% of patients had soft tissue swelling improvement, 82% with improvement in
proptosis, 78% with improved ocular motility restriction and 75% had decreased pain.
Kennerdell et al.[50] showed benefit at doses of 2500 to 3000 cGy over ten days, Sergott et al.[51]
at doses of 1000 to 2000 cGy over 10-15 days and Orcutt et al.[48] at 2500 cGy over 15 days.

Calcineurin inhibitors:
Cyclosporine-A (CsA)

CsA is an im

munosupressent that acts on T-lymphocytes. It inhibits synthesis T-cell growth cytokines, IL-2 and IFN-
γ.[52] A few studies have shown that cyclosporine can be efficacious in diabetic NSOI patients who cannot
tolerate steroids.[2] Diaz-Llopis and Menezo[53] recommend treating NSOI with 5mg/kg/day then tapering
to 2mg/kg/day over ten months. Zacharopoulos et al.[54] treated a patient using 4mg/kg/day for 6 weeks
and this patient remained symptom free for 5 years without any medication.

Tacrolimus

Tacrolimus (Fk506) is very similar to cyclosporine but is approximately 10 times more potent. [55]
Tacrolimus has been shown to be useful for ocular immunosupression,[56][57] but literature regarding
treatment of NSOI has been very limited.

Antiproliferative drugs (Cytotoxic):

Azathioprine

Azathioprine is a mercaptopurine analong which inhibits purine metabolism enzymes. There are only
case reports regarding azathioprine treatment for NSOI. Garrity et al.[45] noted that azathioprine was
ineffective in a patient with vasculitic NSOI, however, Rootman et al.[46] found azathioprine useful in one
patient in conjunction with systemic corticosteroids.

Cyclophosphamide
Cyclophosphamide is a B-cell cytotoxic alkylating agent.[58] There are only limited case reports of
cyclophosphamide used in NSOI. Paris et al.[59] reported effectiveness with pulsed cyclophosphamide
combined with prednisone. Other cases reports have demonstrated durable anti-inflammatory effect for
up to 7 years.[45][59][60] In cases of sclerosing NSOI, Winn and Rootman[61] noted one patient with
improvement with cyclophosphamide but with recurrence 6 years later, another patient with good
response to cyclophosphamide, one that developed recurrence but achieved control with
cyclophosphamide, and one that appeared stable with cyclophosphamide plus colchicine. Adverse drug
reactions include nausea and vomiting, bone marrow suppression, gastrointestinal distress, diarrhea,
alopecia and lethargy.[59][60] Hemorrhagic cystitis can also occur but is prevented by fluid intake and
mesna.[62] A long-term complication can be the development of transitional cell carcinoma of the
bladder.[62]

Methotrexate

Methotrexate is an inhibitor of dihydrofolate reductase, an enzyme needed in folic acid synthesis. This
results in suppression of both T-cell and B-cell functions. Methotrexate is also known to enhance the
release of adenosine, which has potent anti-inflammatory effects.[63] Methotrexate has a long history of
success in the treatment of rheumatoid arthritis.[32] For ocular immunosupression Hemady et al[52]
recommend 10 to 25 mg divided over 36 to 48 hours every 1 to 4 weeks. Smith and Rosenbaum[64]
reported treating seven NSOI patients with methotrexate ranging from 15 to 25 mg/week for periods of
4 weeks to 34 months. Of those seven patients 4 demonstrated clinical benefit, in one patient
methotrexate was stopped due to side effects, in one there was no response, and 2 patients did not
complete the 4 months trial for undisclosed reasons. Shah et al.[65] evaluated methotrexate use in NSOI
at low doses of 12.5 mg/wk and reported 16 out of 22 patients that had a reduction of inflammatory
activity. Fourteen of the 16 patients were able to taper or discontinue corticosteroid therapy and 5
patients had complete remission. Six patients did not response to methotrexate. Prominent side effects
of methotrexate include gastrointestinal disturbances, arthralgias, liver abnormalities, alopecia, fatigue
and headache.[8][63][58][55][64] Dietary supplements of folate, restriction of alcohol intake and parenteral
administration of methotrexate can prevent these side effects.
Cytokine/protein specific biologic agents:

Adalimumab

Adalimumab is a recombinant IgG1 monoclonal antibody containing 100% human peptide sequences
targeting tumor necrosis factor alpha (TNF-α). TNF-α is a cytokinic key factor in the inflammatory
cascade. Adalimumab has been proven to be effective in adult patients with rheumatoid arthritis,
ankylosing spondylitis and psoriatic arthritis.[66][67][68][69] The results of etanercept for eye related diseases
have been mixed. In a randomized, double blind trial of 18 patient with ocular sarcoidosis there was
found to be no therapeutic benefit over placebo.[70] A similar results was reported in the treatment of
JIA uveitis.[64] The Wegener's Granulomatosis Etanercept Trial (WEGET) was a randomized, placebo-
controlled trial where etanercept was evaluated for maintenance of remission in 180 patients. The study
found that etanercept was ineffective, but also those treated with etanercept were found to have a
higher risk of developing solid tumors in comparison with those treated with cyclophosphamide.[71]

Infliximab

Infliximab is a chimeric monoclonal antibody against TNF-α. As infliximab is one of the first
specific agents to be directed against TNF-α, there has been more evidence regarding its use in
variety of ocular disease. It has been so successful in Behçet's disease that it is becoming the
treatment of choice for this disorder.[72][73] There has been increasing body of evidence that
infliximab is a useful therapeutic option in NSOI. Garrity et al.[74] reported the treatment of 7
patients with chronic and refractory orbital myositis. Patients received a dosing schedule of 3 to
5 mg/kg (up to 10 mg/kg) given at weeks 0,2,and 6 with treatments every 4 to 8 weeks
afterwards. It was noted that all 7 patients had a favorable response to treatment with no
untoward effects after a mean follow-up of 15.7 months (range, 4 to 31 months). Miguel et al.[75]
has reported two cases of steroid dependent NSOI who developed adverse effects from
conventional steroid-sparing agents, in both cases symptoms had disappeared with infliximab
with follow-up of at least 20 months. Sahlin et al.[76] described successful treatment of 1 patient
with sclerosing NSOI with combination infliximab and methotrexate therapy. Wilson et al.[77]
has reported success in the treatment in a pediatric patient with refractory bilateral NSOI and has
remained symptom free and off corticosteroids 2 years since initial diagnosis Side effects include
rash, headache, respiratory congestion, hypotension, development of autoantibodies and possible
risk of lymphoma.[78][79][80]

Rituximab
Rituximab is a chimeric mouse-human monoclonal antibody against the protein CD20, which is
primarily found on B-cells as a cell-surface protein. Although ritixumab is a monoclonal
antibody it tends to act more as a cytotoxic agent than other biologic agents.<ref name="Carruth"
/> On et al.<ref name="On">On A, Hirschbien M, Williams H, Karesh J. CyberKnife
radiosurgery and rituximab in the successful management of sclerosing idiopathic orbital
inflammatory disease. Ophthalm Plas Reconstr Surg 2006;22:395-397</ref> first reported the
use of rituximab in the successful management of one patient with refractory NSOI in
combination with CyberKnife radiosurgery with rituximab dosing at 375mg/m2 IV weekly for 4
weeks. Schafranksi[81] reported success with rituximab in one patient with NSOI refractory to
azathioprine therapy, at dosing of two 1000-mg infusions on days 0 and 15. Lastly, Ibrahim et
al.[82] has reported successful treatment one patient with rheumatoid arthritis who developed
NSOI refractory to adalimumab with ritixumab dosing of 1000-mg infusions administered 2
weeks apart. The side effects of rituximab include infusion site reactions, rash, rigors, fever,
headache, infection, and bronchospasm.[58][83]

Tocilizumab

Tocilizumab is an anti-interleukin-6 receptor antibody that has been shown to be effective in the
treatment of systemic-onset juvenile idiopathic arthritis and rheumatoid arthritis.[84][85] A review
of 392 patients with noninfectious anterior scleritis showed 1 patient with successful treatment of
scleritis with Tocilizumab.[86] Tappeiner et al.[87] reported 3 patients with JIA-associated uveitis
that were treated with tocilizumab. Two out of the three patients achieved inactivity of uveitis
while 1 patient required increased in the osage of topical steroids. In all three patients arthritis
improved. To date toclizumab has not been reported in treating NSOI. The most common side
effects of tocilizumab include upper respiratory tract infections, nasopharyngitis, headache,
hypertension, and transient elevation of serum liver enzyme levels.[88] More serious side effects
include neutropenia, serious infection, and thrombocytopenia.[89]

Intravenous Immunoglobulin and Plasmapheresis

Both intravenous immunoglobulin (IVIG) and plasmapheresis act via removal of autoantibodies
by neutralization and filtration, respectively.[55] However, the exact mechanism of action of IVIG
in immune-mediated diseases remains unknown.[90] It has been suggested that IVIG may activate
the inhibitory Fc receptor pathway.[91] In one study, Rosenbaum et al.[92] treated 10 patients with
refractory bilateral uveitis with IVIG and observed sustained and substaintial benefit in 5 out of
the 10 patients for over 11 months. Shambal et al.[93] treated 1 patient with refractory orbital
myositis with .3 g/kg/weight for 3 days and considerable improvement was noted. Symon et
al.[94] reported the successful treatment of resistant NSOI with a total dose of 2g/kg divided over
4 days as an 8-hour infusion with resolution of pain and proptosis. IVIG has also been used
successfully in the thyroid eye disease.[95] There have been no case reports of the use of
plasmapheresis in the treatment of NSOI. IVIG is associated with thromboembolism, aseptic
meningitis and the risk of transmission of blood-borne infection.[90] Despite the promise, IVIG is
a limited resource and, therefore, is an extremely costly therapy. As a result its use should
probably be limited to those who have failed virtually all other available treatments.[90]
Surgical Therapy

Surgical resection can be an effective form of treatment in NSOI refractory to treatment.

However, lesions must be localized for best surgical outcome. For diffuse, fibrotic lesions or
lesions near vital structures surgical resection may not be viable. In an eye with a confirmed
diagnosis of NSOI that becomes blind and painful or is completely refractory to all treatments
exenteration may be considered.[23]

Decision Tree

Step 1: If negative proceed to step 2

Step 2

Outcomes
Outcomes regarding NSOI differ in the literature given the variability in both disease
presentation and treatment protocols. Retrospective data from academic centers may reflect an
overall higher rate of corticosteroid failures than observed in the community as these centers will
generally see more severe or recalcitrant disease.

In 2002, Yuen and Ruben[23] reviewed 65 NSOI patients who were treated at the Massachusetts
Eye and Ear Infirmary from January 1991 to April 2001. Treatment modalities used included
steroids, steroids and radiation, steroids and NSAIDs, radiation and NSAIDs, NSAIDs alone,
surgical debulking and observation only. Five years after Yuen and Rubin, Swamy et al.[7]
published treatment outcomes of 24 patients with biopsy proven NSOI. Therapeutic modalities
included observation alone, antibiotics, oral corticosteroids, intravenous corticosteroids,
adjunctive radiation therapy and systemic immunosuppressive drugs (methotrexate, azathioprine,
mycophenolate, and ciclosporine). Of the 24 patients, 16 (67%) had complete resolution of
symptoms, 4 (17%) had partial resolution and 4 (17%) had no improvement in their symptoms.
In 2012 Pemberton and Fay[96] reviewed all published cases of sclerosing NSOI. Seventeen
articles with 56 biopsy-proven sclerosing NSOI with documented outcomes were reviewed.
There were 15 different treatment regimens including steroids, radiation therapy and
immunomodulatory drugs. Regardless of treatment modality the overall response was good in 19
(34%) patients, partial in 24 (43%), and poor in 13 (23%).