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{{Infobox disease | Name = Nonspecific Orbital Inflammation (Idiopathic orbital inflammation, Orbital inflammatory syndrome, Orbital pseudotumor) | Image = Orbital_Myositis.JPG | Alt = | Caption = Axial CT of NSOI of extraocular muscles (orbital myositis) | DiseasesDB = | ICD10 = {{ICD10|H|05|1|d|10}} | ICD9 = {{ICD9|376.11}} | OMIM = | MeshID = D016727 }} Nonspecific orbital inflammation (NSOI), also known as orbital inflammatory pseudotumor, idiopathic orbital inflammation ( IOI)and orbital inflammatory syndrome is the most common cause of painful orbital mass in adults.<ref name="Weber">Weber AL, Romo LV, Sabates NR. Pseudotumor of the orbit: clinical, pathologic, and radiologic evaluation. Radiol Clin North Am 1999;37:151-168</ref> NSOI can be localized or diffuse. When localized, inflammation can affect the [http://en.wikipedia.org/wiki/Extraocular_muscles extraocular muscles] (orbital myositis), [http://en.wikipedia.org/wiki/Lacrimal_gland lacrimal gland ](dacryoadenitis), [http://en.wikipedia.org/wiki/Sclera sclera] (scleritis), [http://en.wikipedia.org/wiki/Uvea uvea] (uveitis), and the [http://en.wikipedia.org/wiki/Superior_orbital_fissure superior orbital fissure ]and [http://en.wikipedia.org/wiki/Cavernous_sinus cavernous sinus] ([http://eyewiki.aao.org/Tolosa-Hunt_syndrome Tolosa-Hunt syndrome]). Others include periscleritis, perineuritis, and mass. When diffuse, NSOI may diffusely involve the orbital fatty tissues. NSOI is the third most common orbital disease after [http://eyewiki.aao.org/Thyroid_Eye_Disease thyroid eye disease ]and [http://eyewiki.aao.org/Orbital_Lymphoma orbital lymphoma].<ref name="Weber" /> NSOI can both [http://eyewiki.aao.org/Nonspecific_Orbital_Inflammation_(Idiopathic_orbital_inflammation,_Orbital_inflammatory_syndrome,_Orbital_pseudotumor)#Imaging radiologically] and clinically mimic a malignant process. Therefore, it is a diagnosis of exclusion, only after all other causes of inflammation have been eliminated. [http://eyewiki.aao.org/Nonspecific_Orbital_Inflammation_(Idiopathic_orbital_inflammation,_Orbital_inflammatory_syndrome,_Orbital_pseudotumor)#Management Treatment] options are varied and can include surgery, steroids, chemotherapeutic agents and irradiation.<ref name="Narla">Narla LD, Newman B, Spottswood SS, Narla S, Kolli R: Inflammatory Pseudotumor. Radiographics, online publication 2003;23:719-720</ref> = Disease Entity = === '''International Classification of Disease (ICD)''' === [http://en.wikipedia.org/wiki/ICD-9#ICD-9 ICD-9-CM] 376.11 Orbital granuloma [http://en.wikipedia.org/wiki/ICD-10-CM ICD-10-CM] H05.11 Granuloma of orbit === '''History''' === Nonspecific orbital inflammation was first described in 1905 by Birch-Hirschfeld.<ref name="Birch">Birch-Hirschfeld A. Zur Diagnostic and Pathologic der Orbital Tumoren. Bericht uber die Zusammenkunft der Deutschen Ophthalmologischen Gesellschaft 1905;32:127e35.</ref> It was named as inflammatory pseudotumor in 1954 by Umiker et al.<ref name="Umiker">Umiker WO, Iverson LC. Post inflammatory tumor of the lung: report of four cases simulating xanthoma, firboma, or plasma cell granuloma. J. Thorac Surg 1954;28:55-62</ref> because of its propensity to mimic a malignant process. Presently, Nonspecific orbital inflammation and orbital inflammatory pseudotumor can be used interchangeably. === '''Definition''' === NSOI is a benign noninfectious, inflammatory process of the orbit ; characterized by a polymorphous lymphoid infiltrate with varying degrees of fibrosis, without a known local or systemic cause.<ref name="Orbits">Orbits, Eyelids, and Lacrimal System, AAO, BCSC Section 7, 2011-2012 pg. 59</ref> h === '''Incidence''' === The true incidence of NSOI is difficult to assess given the wide range of manifestation and lack of universally accepted definition. NSOI has been shown to account for up to 8-10 % of orbital disorders.<ref name="Yuen">Yuen SJ, Rubin P. Idiopathic orbital inflammation: ocular mechanisms and clinicopathology. Ophthalmol Clin N Am 2002;15:121-126</ref> === Frequency of NSOI subtypes === Swamy et al.<ref name="Swamy">Swamy BN, McCluskey P, Nemet A, Crouch R, Martin P, Benger R, Ghabriel R, Wakefield D. Idiopathic orbital inflammatory syndrome: Clinical features and treatment outcomes. Br J Ophthalmol 2007;91:1667-1670</ref> reviewed 24 patients with biopsy proven NSOI and found that the lacrimal gland was affected 54.2% of the time (13/24), extraocular muscles 50.0% (12/24), orbital fat 75.0% (18/24), sclera 4.2% (1/24), optic nerve 20.8% (5/24) and other 8.3% (2/27). === '''Histopathology''' === The histopathologic spectrum of NSOI is typically non-diagnostic and diverse. The pathogenesis is controversial due to the wide range of presentation ranging from the typical diffuse polymorphous infiltrate to lymphoid, granulomatous, sclerosing, eosinophilic or vasculitic inflammation.<ref name="Espinoza">Espinoza GM. Orbital Inflammatory Pseudotumors: Etiology, Differential, Diagnosis, and Management. Curr Rheumatol Rep 2010;12:443-447</ref>  Reese presented 5 subdivisions<ref name="Reese">Reese AB. Tumors of the eye. New York: Harper; Row; 1951. p. 518</ref> and Farrow proposed 2 classes.<ref name="Henderson">Henderson JW, Farrow GM, editors. Orbital Tumors. Philadelphia: W.J. Saunders Co.; 1973. p.555</ref> However, to date, no one classification scheme has been universally accepted. === '''Pathophysiology''' === The etiology and pathogenesis of NSOI is currently unknown. Both infectious and immune-mediate etiologies have been implicated. Other suggested theory is molecular mimicry when a foreign antigen structural has similarities with self-antigens may happen after an acute infection. NSOI has been observed in association with a variety or rheumatologic conditions including [http://en.wikipedia.org/wiki/Crohn%27s_disease Crohn's disease], [http://en.wikipedia.org/wiki/Systemic_lupus_erythematosus systemic lupus erythematous], [http://en.wikipedia.org/wiki/Rheumatoid_arthritis rheumatoid arthritis], [http://eyewiki.aao.org/Myasthenia_Gravis myasthenia gravis], and [http://en.wikipedia.org/wiki/Spondylitis ankylosing spondylitis].<ref name="Espinoza" /><ref name="SmithJW">Smith JW. Orbital pseudotumor and Crohn’s disease. Am J Gastroenterol 1992;87(3):405-406</ref><ref name="Serop">Serop S, Vianna RN, Claeys M, DE Laey JJ. Orbital myositis secondary to systemic lupus erythematosus. Acta Ophthalmol 1994;72:520-523</ref><ref name="Van de Mosselaer">Van de Mosselaer G, Deuren HV, Dewolf-Peeters C, et al. Pseudotumor orbitae and myasthenia gravis. Arch Ophthalmol 1980;98:1621-1622</ref><ref name="Woo">Woo TL, Francis IC, Wilcsek GA, Coroneo MT, McNab AA, Sullivan TJ. Australian orbital and adnexal Wegner’s granulomatosis. Ophthalmology. 2001;108: 1535-1543</ref> Purcell and Taulbee<ref name="Purcell">Purcell JJ, Taulbee WA. Orbital myositis after upper respiratory tract infection. Arch Ophthalmol 1981;99:437-438</ref> reported a case of new onset orbital myositis within two weeks after confirmed [http://en.wikipedia.org/wiki/Streptococcal_pharyngitis streptococcal pharyngitis]. Mombaerts et al.<ref name="Mombaerts">Mombaerts I, Koornneef L. Current status in the treatment of orbital myositis. Ophthalmology 1997;104(3):402-408</ref> found in their series that 10% of their patients with NSOI also had a concurrent [http://en.wikipedia.org/wiki/Autoimmune_disease autoimmune disease]. In another study by Sobrin et al.<ref name="Sobrin">Sobrin L, Kim E, Christen W et al. Infliximab therapy for the treatment of refractory ocular inflammatory disease. Arch Ophthalmol. 2007;125:895-900</ref>, 21 of 27 patients that were treated with infliximab for ocular inflammation were found to have coincidental rheumatologic disease. Atabay et al.<ref name="Atabay">Atabay C, Tyutyunikov A, Scalise D, et al. Serum antibodies reactive with eye muscle membrane antigens are detected in patients with nonspecific orbital inflammation. Ophthalmology. 1995;102:145-153</ref> reported that circulating [http://en.wikipedia.org/wiki/Antibody antibodies ]against eye muscle [http://en.wikipedia.org/wiki/Antigen antigens ]are present in patients with orbital myositis. They found [http://en.wikipedia.org/wiki/Autoantibody autoantibodies ]active against eye muscle membrane proteins of 55 and 64 kilodaltons which were seen in 63% of the orbital myositis patients compared with 16-20% in healthy patients. It has been proposed that this autoimmunity may be the ocular mechanism for some forms of orbital myositis. However, antibodies to this protein have also been seen in thyroid orbitopathy.<ref name="Atabay" /> Additionally, the typical unilateral presentation of NSOI argues against this type of autoimmunity as being the primary mechanism of NSOI. Mottow-Lippe et al.<ref name="Mottow-Lippa">Mottow-Lippa L, Jakobiec FA, Smith M. Idiopathic inflammatory orbital pseudotumor in childhood II results of diagnostic tests and biopsies. Ophthalmology. 1981;88(6):565-574</ref> suggest that trauma may cause increased vascular permeability resulting in release of antigenic substances which in turn incite an inflammatory cascade. They propose that the variable nature and multi-focality of NSOI can be explained by the network of connective tissue and capillaries delivering antigenic agents to a variety of orbital structures. Wladis et al.<ref name="Wladis">Wladis EJ, Iglesias BV, Gosselin EJ. Characterization of the Molecular Biologic Milieu of Idiopathic Orbital Inflammation. 2011;27:251-254</ref> performed quantitative [http://en.wikipedia.org/wiki/Cytokine cytokine] assays for 9 different molecules and noted that six cytokines were significantly elevated in NSOI ([http://en.wikipedia.org/wiki/Interleukin_2 interleukin-2], [http://en.wikipedia.org/wiki/Interleukin_8 -8], [http://en.wikipedia.org/wiki/Interleukin_10 -10], [http://en.wikipedia.org/wiki/Interleukin_12 -12], [http://en.wikipedia.org/wiki/Gamma_interferon gamma interferon], and [http://en.wikipedia.org/wiki/Tumor_necrosis_factor-alpha tumor necrosis factor alpha]). An animal model has been proposed however more complete models are needed to better understand NSOI pathophysiology and optimum treatment protocol.<ref name="Fries">Fries PD, Fohrman D, Char DH. Phorbol ester-induced orbital myositis. Arch Ophthalmo.l 1987;105:1273-1276</ref>  Interference of CD20, CD25 and [http://en.wikipedia.org/wiki/Toll-like_receptor Toll-like receptors ]may provide the basis for future therapies.<ref name="Wladis1">Wladis EJ, Iglesias BV, Adam AP, Nazeer T, Gosselin EJ. Toll-Like Receptors in Idiopathic Orbital Inflammation. Ophthal Plast Reconstr Surg. 2012;28:273-276</ref> An immune-mediated pathophysiology is strongly suggested by increased cytokines and favorable, rapid responses of inflammation to systemic corticosteroids and other immunosuppressive agents. These therapies will be discussed further in the management section. = Diagnosis = === Clinical Presentation === All patients with suspected NSOI require a full ophthalmic assessment/workup. NSOI is typically characterized by the abrupt onset of pain, [http://en.wikipedia.org/wiki/Proptosis proptosis] and other inflammatory signs such as swelling and erythema. Unilateral presentation is more typical but bilateral presentations are not uncommon.<ref name="Ahn Yuen SJ">Ahn Yuen SJ, Rubin PAD. Idiopathic Orbital Inflammation Distribution, Clinical Features, and Treatment Outcome. Arch Ophthalmol. 2003;121:491-499</ref> Pediatric NSOI differs from the adult presentation and is more commonly characterized by bilateral manifestation, uveitis, disc edema and [http://en.wikipedia.org/wiki/Eosinophilia eosinophilia].<ref name="Berger">Berger JW, Rubin PAD, Jakobiec FA. Pediatric orbital pseudotumor: case report and review of the literature. Int Ophthalmol Clin 1996;36:161-177</ref> Pain is the most common symptom in adult NSOI and occurs 58-69% of the time followed by diplopia (31-38%).<ref name="Berger" /><ref name="Ding">Ding ZX, Lip G, Chong V. Idiopathic orbital pseudotumor. Clinical Radiology 2011;66:886-892</ref> 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%), [http://en.wikipedia.org/wiki/Chemosis chemosis] (29%), decreased vision (20.8%), and [http://en.wikipedia.org/wiki/Ptosis_(eyelid) ptosis] (16.7%).34-35 Therefore, physical examination of patients with suspected NSOI involves lid assessment (retraction/lid lag/[http://en.wikipedia.org/wiki/Lagophthalmos lagophthalmos]), orbital assessment (proptosis), extraocular muscles (restriction), globe (injection/chemosis), and optic nerve function (visual acuity/color plates/[http://en.wikipedia.org/wiki/Afferent_pupillary_defect relative afferent pupillary defect]). Because of the association between rheumatologic disease and NSOI the typical laboratory work-up for suspected NSOI should include a [http://en.wikipedia.org/wiki/Complete_blood_count complete blood count], [http://en.wikipedia.org/wiki/Basic_metabolic_panel basic metabolic panel], [http://en.wikipedia.org/wiki/Thyroid_function_tests thyroid function studies], [http://en.wikipedia.org/wiki/Erythrocyte_sedimentation_rate erythrocyte sedimentation rate], [http://en.wikipedia.org/wiki/Antinuclear_antibody antinuclear antibodies], [http://en.wikipedia.org/wiki/Anti-neutrophil_cytoplasmic_antibody antineutrophil cytoplasmic antibodies], [http://en.wikipedia.org/wiki/Angiotensin-converting_enzyme angiotensin-converting enzyme level], [http://en.wikipedia.org/wiki/Rapid_plasma_reagin rapid plasma reagin test], and [http://en.wikipedia.org/wiki/Rheumatoid_factor rheumatoid factor].<ref name="Espinoza" /> [[Image:Dacryoadenitis1.jpg|center|300x350px]]'''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 [http://en.wikipedia.org/wiki/Computed_tomography high-resolution computed tomography (CT) ]or [http://en.wikipedia.org/wiki/Mri 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.<ref name="Narla" /> MRI is preferred in demonstrating soft tissue changes in the region of the [http://en.wikipedia.org/wiki/Cavernous_sinus cavernous sinus]/superior orbital fissure due to beam hardening and bone streak artifacts seen in CT.<ref name="Kline">Kline LB, Hoyt WF. The Tolosa-Hunt syndrome. J Neurol Neurosurg Psychiatry 2001;71:577-582</ref> Kapur et al.<ref name="Kapur">Kapur R, Sepahdari AR, Mafee MF, et al. MR imaging of orbital inflammatory syndrome, orbital cellulitis, and orbital lymphoid lesions: the role of diffusion-weighted imaging. AJNR Am J Neuroradiol 2009;30:64-70</ref> have noted different intensities diffusion-weighted imaging (DWI) between NSOI, [http://eyewiki.aao.org/Orbital_Cellulitis orbital cellulitis] and orbital lymphoid. Therefore, DWI may help differentiate these entities.<ref name="Kapur" /> Radiologic findings allow subtypes of NSOI to be more precisely classified and are as follows:<ref name="Weber" /><ref name="Ding" /><ref name="Flanders">Flanders Ae, Mafee MF, Rao VM, et al. The characteristics of orbital pseudotumor and other orbital inflammatory processes. J Comput Assist Tomogr 1989;13:40-47</ref><ref name="McKinney">McKinney AM, Short J, Lucato L, et al. Inflammatory myofibroblastic tumor of the orbit with associated enhancement of the meninges and multiple cranial nerves. Am J Neuroradiol 2006;27:2217-2220</ref><ref name="Lee">Lee EJ, Jung Sl, Kim BS, et al. MR imaging of orbital inflammatory pseudotumors with extraorbital extension. Korean J Radiol 2005;6:82-88</ref><ref name="Clifton">Clifton AG, Borgstein RL, Moseley IF, et al. Intracranial extension of orbital pseudotumor. Clin Radiol 1992;45:23-26</ref> ==== 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). [[Image:Dacryoadenitis2.jpg|center|355x300px|Figure 2: Diffusely enlarged right lacrimal gland with blurring of gland margin. Courtesy of Professor M Chua]] 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. [[Image:Orbital Myositis.JPG|center|311x278px|Figure 3: CT image of bilateral medial and lateral rectus tubular-like enlargement with tendon involvement. Courtesy of Z.X. Ding]]'''Figure 3:''' CT image of bilateral medial and lateral rectus tubular-like enlargement with tendon involvement. Courtesy of Z.X. Ding ==== [http://en.wikipedia.org/wiki/Optic_nerve 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. [[Image:NSOI optic nerve tramline.JPG|center|326x265px|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]]'''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, [http://en.wikipedia.org/wiki/Tenon%27s_capsule Tenon's capsule], and uvea: ==== Imaging will demonstrate non-specific thickening of structures. Blurring of the sclera margin may be seen (Figure 5). [[Image:NSOI Uveoscleral.JPG|center|320x235px|Figure 5: CT image showing thickening and blurring of left eye uveoscleral (asterisks). Courtesy of Z.X. Ding]] '''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). [[Image:NSOI Orbital fat.JPG|center|335x223px|Figure 6: CT image showing enhancement of orbital fat (asterisks). Courtesy of Z.X. Ding]]'''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 [http://en.wikipedia.org/wiki/Middle_cranial_fossa 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 [http://en.wikipedia.org/wiki/Meninges meninges] contiguous with the orbital inflammation. [[Image:NSOI cavernous sinus.JPG|center|314x264px|Figure 7: MRI, fat-saturated, T1-weighted image with white arrows showing extension into the cavernous sinus. Courtesy of Z.X. Ding]]'''Figure 7:''' MRI, fat-saturated, T1-weighted image with white arrows showing extension into the cavernous sinus. Courtesy of Z.X. Ding   === Biopsy === A major of debate whether orbital biopsy indicated or not. There may be not be a distinct mass to biopsy or the lesion may be unapproachable and response to therapy can be confirmatory.<ref name="Jacobs">Jacobs D, Galetta S. Diagnosis and management of orbital pseudotumor. Curr Opin Ophthalmol 2002;13:347-351</ref> Biopsy may be considered if there are progressive neurologic deficits, lack of steroid responsiveness and persistent imaging abnormalities. [[Image:Dacryoadenitis 3.jpg|center|340x212px|Figure 8: Showing whitish infiltration of the lacrimal gland on direct upper eyelid incision, Courtesy of Professor M Chua]]'''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.<ref name="Dutton">Dutton JJ. Orbit and lacrimal gland. In: Yanoff M, Duker JS, editors. Ophthalmology. Mosby, Inc., St. Louis, 2004, p.729-743</ref> Orbital cellulitis risk factors include history of [http://en.wikipedia.org/wiki/Sinusitis sinusitis], dental work/disease, or trauma.<ref name="Israele">Israele V, Nelson JD. Periorbital and orbital cellulitis. Ped Infect Dis J 1987;6:404-410</ref><ref name="Mawn">Mawn LA, Jordan DR, Donahue SP. Preseptal and Orbital Cellulitis. Ophthalmol Clin N Am 2000;13:633-41</ref> Table 1 outlines common differential diagnosis for NSOI. [[Image:NSOI Differential Diagnosis.png|center|856x393px|Table 1: Differential Diagnosis of Orbital Inflammation]]'''Table 1: '''Differential Diagnosis of Orbital Inflammation<ref name="Espinoza" /><ref name="Ding" /><ref name="Jacobs" /><ref name="Mawn" /><ref name="Lutt">Lutt JR, Lim L, Phal PM, Rosenbaum JT. Orbital Inflammatory Disease. Semin Arthritis Rheum 2008;37:207-222</ref><ref name="Watkins">Watkins LM, Carter KD, Nerad JA. Ocular Adnexal Lymphoma of the Extraocular Muscles: Case Series From the University of Iowa and Review of the Literature. Ophthal Plast Reconstr Surg. 2011;27:471-476</ref><ref name="Ahmad">Ahmad MS, Esmaeli B. Metastatic tumors of the orbit and ocular adnexa. Curr Opin Ophthalmol 2007;18:405-413</ref><ref name="Tarabishy">Tarabishy AB, Schulte M, Papaliodis GN, Hoffman GS. Wegener’s Granulomatosis: Clinical Manifestations, Differential Diagnosis, and Management of Ocular and Systemic Disease. Surv Ophthalmol 2010;5:429-444</ref><ref name="Prabhakaran">Prabhakaran VC, Saeed P, Esmaeli B et al. Orbital and Adnexal Sarcoidosis. Arch Ophthalmol 2007;125(12):1657-1662</ref><ref name="Nageswaran">Nageswaran S, Woods CR, Benjamin DK, Givner LB, Shetty AK. Orbital Cellulitis in Children. Pediatr Infect Dis J 2006;25:695-699</ref><ref name="Cockerham">Cockerham KP, Chan SS. Thyroid Eye Disease. Neurol Clin 2010;28:729-755</ref> = Management = === Observation === Observation for NSOI for mild cases of inflammation may be acceptable. Swamy et al.<ref name="Swamy" /> 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) === [http://en.wikipedia.org/wiki/Non-steroidal_anti-inflammatory_drug 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.<ref name="Mannor">Mannor GE, Rose GE, Moseley IF, et al. Outcome of orbital myositis: clinical features associated with recurrence. Ophthalmology 1997;104:409-414</ref> 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 [http://en.wikipedia.org/wiki/Dyspepsia dyspepsia ]which can be reduced through suppressing acid production, via a [http://en.wikipedia.org/wiki/Proton-pump_inhibitor proton pump inhibitor], e.g. omeprazole or esomeprazole.<ref name="Green">Green GA. Understanding NSAIDs: from aspiring to COX-2. Clinical cornerstone 2001;3:50-60</ref> === Corticosteroids === Systemic [http://en.wikipedia.org/wiki/Corticosteroids corticosteroids] are generally considered mainstay therapy for NSOI with its both anti-inflammatory effect ( by inhibition of phospholipase A2 and cyclooxygenase pathways) and immunosuppressive effect ( by inhibition of IL, IFN synthesis,cytotoxic effect on T lymphocytes, and inhibition of major histocompatibility antigen expression) .<ref name="Espinoza" /><ref name="Jacobs" /> 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<ref name="Ahn Yuen SJ" /> found that 69% were treated with steroids alone, 12% with steroids and radiation therapy and 9% with steroids and NSAIDs. Yuen and Ruben<ref name="Ahn Yuen SJ" /> 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><ref name="Garrity">Garrity JA, Kennerdell JS, Johnson BL, et al. Cyclophosphamide in the treatment of orbital vasculitis. Am J OphthalmoI 1986;102:97-103</ref> 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 === [http://en.wikipedia.org/wiki/Radiation_therapy Radiation therapy] the commonly used is external beam radiotherapy can be used in the treatment of NSOI as an alternative or adjuvant. It is generally used when NSOI is found to be resistant to or intolerant to corticosteroid therapy.<ref name="Rootman">Rootman J, McCarthy M, White V, et al. Idiopathic sclerosing inflammation of the orbit: a distinct clinicopathological entity. Ophthalmology 1994;101:570-584</ref> The results of radiotherapy have been reported to have success rates ranging between 50-75%.<ref name="Lanciano">Lanciano R, Fowble B, Sergott RC, et al. The results of radiotherapy for orbital pseudotumor. Int J Radiat Oncol Biol Phys 1990;18:407-411</ref><ref name="Orcutt">Orcutt J, Garner A, Henk J, Wright J. Treatment of idiopathic inflammatory orbital pseudotumors by radiotherapy. Br J Ophthalmol 1983;67:570-574</ref> Other authors have published greater long-term control to ranging from 66%-100% success after a total dosage of 2000 cGy.<ref name="Lanciano" /><ref name="Smitt">Smitt MC, Donaldson SS. Radiation therapy for benign disease of the orbit. Semin Rad Oncol 1999;9:179-189</ref> In there review of 24 NSOI patients treated with radiation therapy, Lanciano et al.<ref name="Lanciano" /> 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.<ref name="Kennerdell">Kennerdell J, Johnson B, Deutsch M. Radiation treatment of orbital lymphoid hyperplasia. Ophthalmology 1979;86:942-947</ref> showed benefit at doses of 2500 to 3000 cGy over ten days, Sergott et al.<ref name="Sergott">Sergott R, Glaser J, Charyulu K. Radiotherapy for idiopathic inflammatory orbital pseudotumor: indications and results. Arch Ophthalmol 1981;99:8536</ref> at doses of 1000 to 2000 cGy over 10-15 days and Orcutt et al.<ref name="Orcutt" /> at 2500 cGy over 15 days. keep in mind the acute and chronic side effects of radiation such as dry eye,periocular dermatitis, keratitis, cataract, optic neuropathy and retinopathy. === Calcineurin inhibitors: === ==== Cyclosporine-A (CsA) ==== CsA is an im[[Image:Ciclosporin-A-neutron-3D-sticks.png|left|150x75px]]munosupressent that acts on [http://en.wikipedia.org/wiki/T-lymphocytes T-lymphocytes]. It inhibits synthesis T-cell growth cytokines, IL-2 and IFN-γ.<ref name="Hemady">Hemady R, Tauber J, Foster CS. Immunosupressive drugs in immune and inflammatory ocular disease. Surv Ophthalmol. 1991;35:369-385</ref> A few studies have shown that cyclosporine can be efficacious in diabetic NSOI patients who cannot tolerate steroids.<ref name="Narla" /> Diaz-Llopis and Menezo<ref name="Diaz-Llopez">Diaz-Llopez M, Menezo JL. Idiopathic inflammatory orbital pseudotumor and low-dose cyclosporine. Am J Ophthalmol 1989;107:547-548</ref> recommend treating NSOI with 5mg/kg/day then tapering to 2mg/kg/day over ten months. Zacharopoulos et al.<ref name="Zacharopoulos">Zacharopoulos IP, Papadaki T, Manor RS, Briscoe D. Treatment of idiopathic orbital inflammatory disease with cyclosporine-A: a case presentation. Semin Ophthalmol 2009 2009;24:260-261</ref> treated a patient using 4mg/kg/day for 6 weeks and this patient remained symptom free for 5 years without any medication. ==== Tacrolimus ==== [[Image:Tacrolimus-3D-sticks.png|left|90x85px]]Tacrolimus (Fk506) is very similar to cyclosporine but is approximately 10 times more potent.<ref name="Chiu">Chiu CS, Rubin PAD. Pharmacotherapies and Nonpharmacotherapies for Orbital Inflammatory Diseases. Int Ophthalmol Clin 2004;44(3):165-185</ref> Tacrolimus has been shown to be useful for ocular immunosupression,<ref name="Abeysiri">Abeysiri P, Johnston NR, Molteno ACB. The Use of Topical Tacrolimus 0.1% Skin Ointment for Anterior Segment Conditions: A Case Series. Ophthalmology and Eye Diseases 2010;2:5-8</ref><ref name="Kymionis">Kymionis GD, Kankariya VP, Kontadakis GA. Tacrolimus ointment 0.03% for treatment of refractory childhood phlyctenular keratoconjunctivitis. Cornea 2012;31(8):950-952</ref> but literature regarding treatment of NSOI has been very limited. === Antiproliferative drugs (Cytotoxic): === ==== Azathioprine ==== [[Image:Azathioprine 3d structure.png|left|85x75px]]Azathioprine is a [http://en.wikipedia.org/wiki/Mercaptopurine mercaptopurine] analong which inhibits [http://en.wikipedia.org/wiki/Purine purine] metabolism enzymes. There are only case reports regarding azathioprine treatment for NSOI. Garrity et al.<ref name="Garrity" /> noted that azathioprine was ineffective in a patient with vasculitic NSOI, however, Rootman et al.<ref name="Rootman" /> found azathioprine useful in one patient in conjunction with systemic corticosteroids. ==== Cyclophosphamide ==== [[Image:R-cyclophosphamide-from-xtal-1996-3D-balls.png|left|65x100px]]Cyclophosphamide is a B-cell cytotoxic alkylating agent.<ref name="Carruth">Carruth BP, Wladis EJ. Inflammatory modulators and biologic agents in the treatment of idiopathic orbital inflammation. Curr Opin Ophthalmol 2012;23:420-426</ref> There are only limited case reports of cyclophosphamide used in NSOI. Paris et al.<ref name="Paris">Paris GL, Waltuch GF, Egbert PR. Treatment of refractory orbital psuedotumours with pulsed chemotherapy. Ophthal Plast Reconstr Surg 1990;6:96-101</ref> reported effectiveness with pulsed cyclophosphamide combined with prednisone. Other cases reports have demonstrated durable anti-inflammatory effect for up to 7 years.<ref name="Garrity" /><ref name="Paris" /><ref name="Eagle">Eagle K, King A, Fisher C, Souhami R. Cyclophosphamide induced remission in relapsed, progressive idiopathic orbital inflammation (PSeudotumor). Clin Oncol 1995;7:402-404</ref> In cases of sclerosing NSOI, Winn and Rootman<ref name="Winn">Winn BJ, Rootman J. Sclerosing Orbital Inflammation and Systemic Disease. Ophthal Plast Reconstr Surg 2012;28(2):107-118</ref> 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 [http://en.wikipedia.org/wiki/Colchicine colchicine]. Adverse drug reactions include nausea and vomiting, bone marrow suppression, gastrointestinal distress, diarrhea, [http://en.wikipedia.org/wiki/Alopecia alopecia] and [http://en.wikipedia.org/wiki/Lethargy lethargy].<ref name="Paris" /><ref name="Eagle" /> [http://en.wikipedia.org/wiki/Hemorrhagic_cystitis Hemorrhagic cystitis] can also occur but is prevented by fluid intake and [http://en.wikipedia.org/wiki/Mesna mesna].<ref name="Lawson">Lawson M, Vasilaras A, De Vries A, Mactaggart P, Nicol D. Urological implication of cyclophosphamide and ifosfamide. Scand J Urol Nephrol 2008;42(4):309-317</ref> A long-term complication can be the development of [http://en.wikipedia.org/wiki/Transitional_cell_carcinoma transitional cell carcinoma] of the bladder.<ref name="Lawson" /> ==== Methotrexate ==== [[Image:Methotrexate-3D-balls-1U72.png|left|100x110px]]Methotrexate is an inhibitor of [http://en.wikipedia.org/wiki/Dihydrofolate_reductase 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 [http://en.wikipedia.org/wiki/Adenosine adenosine], which has potent anti-inflammatory effects.<ref name="Gordon">Gordon LK. Orbital inflammatory disease: a diagnostic and therapeutic challenge. Eye 2006;20:1196-1206</ref> Methotrexate has a long history of success in the treatment of rheumatoid arthritis.<ref name="Jacobs" /> For ocular immunosupression Hemady et al<ref name="Hemady" /> recommend 10 to 25 mg divided over 36 to 48 hours every 1 to 4 weeks. Smith and Rosenbaum<ref name="Smith">Smith JR, Rosenbaum JT. A role for methotrexate in the management of non-infectious orbital inflammatory disease. Br J Ophthalmol 2001;85:1220-1224</ref> 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.<ref name="Shah">Shah SS, Lowder CY, Schmitt MA, et al. Low-dose methotrexate therapy for ocular inflammatory disease. Ophthalmology 1992;99:1419-1423</ref> 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, [http://en.wikipedia.org/wiki/Arthralgia arthralgias], liver abnormalities, alopecia, fatigue and headache.<ref name="Espinoza" /><ref name="Gordon" /><ref name="Carruth" /><ref name="Chiu" /><ref name="Smith" /> Dietary supplements of folate, restriction of alcohol intake and [http://en.wikipedia.org/wiki/Parenteral parenteral] administration of methotrexate can prevent these side effects. === Cytokine/protein specific biologic agents: === ==== Adalimumab ==== [[Image:Adalimumab structure.png|left|100x100px]]Adalimumab is a recombinant [http://en.wikipedia.org/wiki/IgG1 IgG1] [http://en.wikipedia.org/wiki/Monoclonal monoclonal] antibody containing 100% human peptide sequences targeting [http://en.wikipedia.org/wiki/Tumor_necrosis_factor-alpha 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.<ref name="Yue">Yue C, You X, Zhao L et al. The effects of adalimumab and methotrexate treatment on peripheral Th17 cells and IL-17/IL-6 secretion in rheumatoid arthritis patients. Rheumatol Int 2010;30(12):1553–1557</ref><ref name="Rudwaleit">Rudwaleit M, Claudepierre P, Wordsworth P et al. Effectiveness, safety, and predictors of good clinical response in 1250 patients treated with adalimumab for active ankylosing spondylitis. J Rheumatol 2009;36(4):801–808</ref><ref name="Philip">Philip J, Mease MD, Bernard S, et al. Etanercept in the treatment of psoriatic arthritis and psoriasis: a randomised trial The Lancet 2000;356(9227):385-390</ref><ref name="Brandt">Brandt J, Kharioouzov A, Listing J, et al. Six-Month Results of a Double-Blind, Placebo-Controlled Trial of Etancercept Treatment in Patients With Active Ankylosing Spondylitis. Arthritis & Rheumatism 2003;48(6):1667-1675</ref> The results of etanercept for eye related diseases have been mixed. In a randomized, double blind trial of 18 patient with ocular [http://en.wikipedia.org/wiki/Sarcoidosis sarcoidosis] there was found to be no therapeutic benefit over placebo.<ref name="Baughman">Baughman RP, Lower EE, Bradley DA, et al. Etanercept for refractory ocular sarcoidosis: results of a double-blind randomized trial. Chest 2005;128:1062-1147</ref> A similar results was reported in the treatment of JIA uveitis.<ref name="SmithJA">Smith JA, Thompson DJS, Whitcup SM, et al. A randomized, placebo controlled, double masked clinical trial of etanercept for the treatment of uveitis associated with juvenile idiopathic arthritis. Arthritis Rheum 2005;53:18-23</ref> The [http://en.wikipedia.org/wiki/Wegener%27s_granulomatosis 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.<ref name="Wegener's">Wegener’s Granulomatosis Etanercept Trial (WGET) Research Group. Etanercept plus standard therapy for Wegener’s granulomatosis. N Engl J Med 2005;352:351-361.</ref> ==== 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 [http://en.wikipedia.org/wiki/Behcets Behçet's disease] that it is becoming the treatment of choice for this disorder.<ref name="Ohno">Ohno S, Nakamura S, Hori S, et al. Efficacy, safety, and pharmacokinetics of multiple administration of infliximab in Behcet's disease with refractory uveoretinitis. J Rheumatol 2004;31(7):1362-1368</ref><ref name="Capella">Capella MJ, Foster CS Long-term efficacy and safety of infliximab in the treatment of Behçet's disease. Ocular Immunology and Inflammation 2012;20(3):198-202</ref> There has been increasing body of evidence that infliximab is a useful therapeutic option in NSOI. Garrity et al.<ref name="Garrity2">Garrity JA, Coleman AW, Matteson EL, et al. Treatment of Recalcitrant Idiopathic Orbital Inflammation (Chronic Orbital Myositis) With Infliximab. Am J Ophthalmol 2004;138:925-930</ref> 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.<ref name="Miguel">Miguel T, Abad S, Badelon I, Vignal C, et al. Successful treatment of idiopathic orbital inflammation with infliximab: An alternative to conventional steroid-sparing agents. Ophthal Plast Reconstr Surg 2008;24(5):415-417</ref> 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.<ref name="Sahlin">Sahlin S, Lignell B, Williams M, et al. Treatment of idiopathic sclerosing inflammation of the orbit (myositis) with infliximab. Acta Ophthalmol 2009;87:906-908</ref> described successful treatment of 1 patient with sclerosing NSOI with combination infliximab and methotrexate therapy. Wilson et al.<ref name="Wilson">Wilson MW, Shergy WJ, Haik BG. Infliximab in the Treatment of Recalcitrant Idiopathic Orbital Inflammation. 2004;20(5):381-399</ref> 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, [http://en.wikipedia.org/wiki/Hypotension hypotension], development of autoantibodies and possible risk of lymphoma.<ref name="Ricart">Ricart E, Panaccione R, Loftus EV, Tremaine WJ, Sandborn WJ. Inﬂiximab for Crohn’s disease in clinical practice at the Mayo Clinic: the ﬁrst 100 patients. Am J Gastroenterol 2001;96:722–729</ref><ref name="Olsen">Olsen NJ, Stein CM. New drugs for rheumatoid arthritis. N Engl J Med 2004;350:2167–2179</ref><ref name="Antoni">Antoni C, Braun J. Side effects of anti-TNF therapy: current knowledge. Clin Exp Rheumatol 2002;20(Suppl 28):S152–S157</ref> ==== Rituximab ==== Rituximab is a chimeric mouse-human monoclonal antibody against the protein [http://en.wikipedia.org/wiki/CD20 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<ref name="Schafranski">Schafranski. Idiopathic orbital inflammatory disease successfully treated with rituximab. Clin Rheumatol 2009;28:225-226</ref> 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.<ref name="Ibrahim">Ibrahim I, Barton A, Ibrahim A, Ho P. Idiopathic Orbital Inflammation Successfully treated Using Rituximab in a Patient with Rheumatoid Arthritis. J Rheumatol 2012;39(7):1485-1486</ref> 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, [http://en.wikipedia.org/wiki/Rigors rigors], fever, headache, infection, and [http://en.wikipedia.org/wiki/Bronchospasm bronchospasm].<ref name="Carruth" /><ref name="Esmaeli">Esmaeli B, Murray JL, Ahmadi MA, et al. Immunotherapy for low-grade non-Hodgkin secondary lymphoma of the orbit. Arch Ophthalmol 2002;120:1225–7</ref> ==== 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.<ref name="Yokota">Yokota S, Imagawa T, Mori M, et al. Efficacu and safety of tocilizumab in patients with systemic-onset juvenile idiopathic arthritis: a randomized, double-blind, placebo-controlled, withdrawal phase III trial. Lancet 2008;371:998-1006</ref><ref name="Nishimoto">Nishimoto N, Yoshizaki K, Miyasaka N, et al. Treatment of rheumatoid arthritis with humanized antiinterleuken-6 receptor antibody: a multicenter, double blind, placebo-controlled trial. Arthritis Rheum 2004;50:1761-1769</ref> A review of 392 patients with noninfectious anterior scleritis showed 1 patient with successful treatment of scleritis with Tocilizumab.<ref name="de la Maza">de la Maza MS, Molina N, Gonzalez-Gonzalez, et al. Scleritis Therapy. Ophthalmology 2012;119:51-58</ref> Tappeiner et al.<ref name="Tappeiner">Tappeiner C, Heinz C, Ganser G. Is Tocilizumab an Effective Option for Treatment of Refractory Uveitis Associated with Juvenile Idiopathic Arthritis? J Rheumatol 2012;39(6):1294-1295</ref> 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, [http://en.wikipedia.org/wiki/Nasopharyngitis nasopharyngitis], headache, hypertension, and transient elevation of serum liver enzyme levels.<ref name="Venkiteshwaran">Venkiteshwaran A. Tocilizumab. MAbs 2009;1:432-8</ref> More serious side effects include neutropenia, serious infection, and thrombocytopenia.<ref name="Oldfield">Oldﬁeld V, Dhillon S, Plosker GL. Tocilizumab: a review of its use in the management of rheumatoid arthritis. Drugs 2009;69:609--32</ref> === Intravenous Immunoglobulin and Plasmapheresis === Both intravenous immunoglobulin (IVIG) and plasmapheresis act via removal of autoantibodies by neutralization and filtration, respectively.<ref name="Chiu" /> However, the exact mechanism of action of IVIG in immune-mediated diseases remains unknown.<ref name="Lim">Lim L, Suhler EB, Smith JR. Biologic therapies for inflammatory eye disease. Clin and Exper Ophthalmol 2006;34:365-374</ref> It has been suggested that IVIG may activate the inhibitory Fc receptor pathway.<ref name="Samuelsson">Samuelsson A, Towers TL, Ravetch JV. Anti-inﬂammatory activity of IVIG mediated through the inhibitory Fc receptor. Science 2001;291:484–486</ref> In one study, Rosenbaum et al.<ref name="Rosenbaum">Rosenbaum JT, George RK, Gordon C. The treatment of refractory uveitis with intravenous immunoglobulin. Am J Ophthalmol 1999;127:545–549.</ref> 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.<ref name="Shambal">Shambal S, Lindner A, Zierz S. Successful treatment of orbital myositis with intravenous immunoglobulins. Muscle Nerve. 1998;21:1359-1360</ref> treated 1 patient with refractory orbital myositis with .3 g/kg/weight for 3 days and considerable improvement was noted. Symon et al.<ref name="Symon">Symon Z, Schneebaum N, Eyal A, et al. Successful Intravenous Immunoglobulin Therapy for Resistant Inflammatory Pseudotumor of the Orbit. Thyroid 2005;14(4):398-399</ref> 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.<ref name="Baschieri">Baschieri L, Antonelli A, Nardi S, Alberti B, Lepri A, Canapicchi R, Fallahi. Intravenous immunoglobulin versus corticosteroid in treatment of Graves’ ophthalmopathy. Thyroid 1997;7:579–585.</ref> There have been no case reports of the use of plasmapheresis in the treatment of NSOI. IVIG is associated with [http://en.wikipedia.org/wiki/Thromboembolism thromboembolism], [http://en.wikipedia.org/wiki/Aseptic_meningitis aseptic meningitis] and the risk of transmission of blood-borne infection.<ref name="Lim" /> 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.<ref name="Lim" /> === 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.<ref name="Ahn Yuen SJ" /> === Decision Tree === [[Image:NSOI Step 1.png|center|734x313px|Step 1: If negative proceed to step 2]]'''Step 1: If negative proceed to step 2''' [[Image:NSOI Step 2.png|center|384x678px|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<ref name="Ahn Yuen SJ" /> reviewed 65 NSOI patients who were treated at the [http://www.masseyeandear.org/ 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.<ref name="Swamy" /> 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<ref name="Pemberton">Pemberton JD, Fay A. Idiopathic Sclerosing Orbital Inflammation: A Review of Demographics, Clinical Presentation, Imaging, Pathology, Treatment, and Outcome. Ophthal Plast Reconstr Surg 2012;28:79-83</ref> 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%). = Discussion = NSOI is diagnosis of exclusion and is highly variable. Given the variable nature of the disease and the emergence of immunosuppresive drugs many therapeutic regimens exist. Retrospective studies have demonstrated that patients on average have symptomatic improvement. It is generally agreed upon that steroids are the initial treatment of choice for moderate to severe NSOI. = Additional Resources = 1. http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002590/ 2. http://www.nlm.nih.gov/medlineplus/ency/article/001623.htm 3. http://en.wikipedia.org/wiki/Idiopathic_orbital_inflammatory_disease = References = <references />
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