Pediatric Orbital Inflammatory Disorders

A. Nonspecific orbital inflammation

 Idiopathic orbital inflammation (based on anatomic location of inflammation) [1–3]

  Myositis (inflammation of an extraocular muscle)

  Dacryoadenitis (inflammation of the lacrimal gland)

  Peribulbar (posterior scleritis, Tenonitis)

  Orbital fat

  Orbital apex

  Cavernous sinus (presumed Tolosa-Hunt syndrome)a


B. Specific orbital inflammation


 ANCA-associated vasculitis:

  Granulomatosis with polyangiitis (Wegener granulomatosis)

  Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome)

 Thyroid eye disease

 Sjögren syndrome (typically as a dacryoadenitis)

 IgG4-related orbitopathy (including IgG4-related dacryoadenitis)

 Orbital xanthogranulomatosis with adult-onset asthmab

 Histiocytic disorders:

  Langerhans cell histiocytosis

   Unifocal (eosinophilic granuloma)

   Multifocal unisystem (Hand-Schüller-Christian variant)

   Multifocal multisystem (Letterer-Siwe disease)

  Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease)

  Polyostotic sclerosing histiocytosis (Erdheim-Chester disease)

 Medication-related (e.g. bisphosphonates, implimumab)


  Inflammatory bowel disease (ulcerative colitis, Crohn disease)

  Systemic lupus erythematosus

  Polyarteritis nodosa

C. Orbital disorders that may mimic noninfectious orbital inflammation

 Orbital infections:

  Bacterial cellulitis, abscess, mucopyocele

  Fungal (especially sino-orbital aspergillosis

  Viral (especially dacryoadenitis associated with Epstein-Barr virus)

 Occult orbital foreign bodies (especially wood)

 Ruptured dermoid cyst


 Leukemic infiltrate/granulocytic sarcoma

 Metastasis (in children, especially neuroblastoma)

 Lymphangioma/venolymphatic malformation (especially with acute intralesional hemorrhage

 Lymphocytic lesions (reactive and malignant)

A. Classification schema for idiopathic orbital inflammation (IOI). B. Specific orbital inflammation (listed as estimation from most to least common). C. Other disorders that may mimic orbital inflammation

aNot considered as part of IOI spectrum by some experts

bUsually a disorder of adults

This chapter will review our current understanding of pediatric orbital inflammatory disease and treatment.

Idiopathic Orbital Inflammation

Idiopathic orbital inflammation [46] (IOI) is a term used to describe a syndrome of nonspecific inflammation of orbital tissue with no identifiable local or systemic cause. This condition was first described by Birch-Hirschfeld in 1905, who coined the term “pseudotumor ” [7]. Numerous other names have been proposed for this group of disorders, including idiopathic inflammatory syndrome, inflammatory orbital pseudotumor , and nonspecific orbital inflammatory syndrome [810]. IOI is currently a diagnosis in transition, as improving diagnostic capabilities have chipped away at what was once “idiopathic” or “nonspecific”. Sarcoidosis, granulomatosis with polyangiitis (GPA, Wegener granulomatosis), thyroid eye disease (TED), IgG4-related inflammation (IgG4-RD), Sjögren syndrome, systemic lupus erythematosus, and histiocytic syndromes (Erdheim-Chester and Rosai-Dorfman diseases) are no longer included under the umbrella term “nonspecific”; they are now classified as specific orbital inflammations with their own immunologic or histopathologic markers. Table 34.1 summarizes a common classification scheme of IOI, the more common types of specific orbital inflammations, and other disease entities which may mimic IOI and should therefore be considered in the differential diagnosis.

Although IOI is grouped among the more common orbital disorders in adults, it is postulated to be rare in the pediatric population. Early studies demonstrated that patients under the age of 18–20 years comprise between 6.6% and 16% of all IOI patients [1113].


Our understanding of the etiology of IOI has benefited from recent advances in immunologic and histopathologic abilities to identify and measure cytokines and antibodies. The classic signs and symptoms of IOI presumably represent the clinical manifestation of one or more autoimmune and cell-mediated processes, the triggers for which are a source of current scrutiny. A “pathologic construct” proposed by Dr. Gerald Harris has correlated specific cells present in surgical specimens with particular clinical symptoms [5]. For example, macrophages activated by pro-inflammatory cytokines cause lysis of cells, escalating a cascade of inflammation and causing tissue injury and fibrosis which can result in the clinical symptoms of orbital pain, swelling, and impaired function [5].

More recently, Wladis and colleagues have demonstrated that gamma interferon and interleukin-12 levels are markedly elevated in IOI when compared to normal, noninflamed tissue profiles and that IOI may be a T-cell-mediated phenomenon [14]. The results of further studies should not only contribute to our understanding of the pathology of IOI, but also may identify targets for treatment with specific biologic agents.


The classic presentation of IOI includes the abrupt onset, often over the course of hours, of periorbital pain accompanied by eyelid edema, erythema, and chemosis (Fig. 34.1). Other common features include proptosis, diplopia, and visual changes. When supported by positive findings on appropriate imaging studies and in the absence of any other identifiable cause, this clinical presentation is considered by some to be diagnostic.


Fig. 34.1
IOI . A 13-year-old boy presented with acute onset of left periorbital pain, swelling, and diplopia. (a, b) External appearance with limitation of upgaze. Note that the swelling is boggy but not tense and pink rather than the typical red of bacterial infection. (c) Conjunctival chemosis and injection. (d) On coronal CT, soft tissue window, a poorly circumscribed intraconal opacification is present surrounding the optic nerve. Note that the paranasal sinuses are clear

In contrast to adults, pediatric patients are more likely to present with bilateral disease [13, 1517] (Fig. 34.2) and ptosis [18]. Constitutional signs and symptoms, such as headache, fever, and malaise, may also be more common in children [15, 1820], and children are more likely to have recurrent disease [1, 15]. Although pain is reported in over 75% [1] of adult patients with IOI, two recent cohort studies suggest that periorbital pain may not be a meaningful indicator of IOI in children, reported in only 17% and 57% of cases, similar to other inflammatory processes [18, 19].


Fig. 34.2
IOI . An 11-year-old girl presented with sudden onset of right upper eyelid edema, neck swelling, and low-grade fever. She had a mildly elevated white count with eosinophilia. (a) External appearance. Note the lack of eyelid erythema. (b) Conjunctival thickening suggestive of the classic “salmon patch” seen in periocular lymphoproliferative disease.Fig. 34.6 (continued) (c) Axial CT, soft tissue window. Note the diffuse enlargement of the right lacrimal gland with spillover into the adjacent eyelid tissue. The ethmoidal sinuses are clear. (d) Axial CT, soft tissue window, of the lower face/upper neck shows enlargement of the parotid gland and cervical submandibular lymph nodes. Tissue biopsy revealed nonspecific inflammation consistent with IOI. All symptoms resolved within 48 h of intravenous corticosteroid infusion

Many of the signs and symptoms of pediatric IOI mimic those of infection. Since orbital infection is the most common cause of acute proptosis in children and has the potential for rapid progression, it is of paramount importance to rule out an infectious etiology (especially orbital spread of adjacent paranasal sinusitis) in all patients with suspected IOI (Fig. 34.1d).

The initial symptoms and signs of IOI in children are summarized in Table 34.2.

Table 34.2
Most common initial symptoms and signs of idiopathic orbital inflammation in pediatric patients [12, 1820]

Signs and Symptoms


Lid swelling




Extraocular motility disorders




Conjunctival injection and/or chemosis


Globe displacement


Palpable mass




Iritis, photophobia


Pain on eye movements


Lid erythema, warmth


Pupillary involvement


Vision loss


Orbital Imaging

Dedicated orbital imaging is an essential part of the diagnostic protocol for any orbital process. Imaging may be by either CT or MRI, although both modalities are associated with drawbacks particular to the pediatric population.

The preferred orbital imaging modality for the evaluation of suspected pediatric IOI remains orbital computed tomography (CT). CT is easily available, images surrounding bone in detail, and provides adequate soft tissue information. When possible, intravenous contrast should be used. Pediatric CT protocols are essential to minimize radiation exposure. Orbital inflammatory lesions have a common radiologic characteristic of an irregular margin adjacent to the focus of the inflammation, despite a variable location of involvement in the orbit, aptly described by Jakobiec as “crabgrass in the orbit”, especially when the process involves the intraconal fat [2, 8]. The involved tissues usually enhance with contrast media. Bone destruction or hypertrophy is not seen in IOI and would suggest malignancy or infection. Adjacent paranasal sinus opacification is not often seen, even though IOI may follow an upper respiratory infection (Figs. 34.1d and 34.2c); the presence of sinus opacification raises the possibility of an infectious etiology. Multi-scan CT techniques permit superb views in all planes from a rapid (<60 s) scan in the supine position.

Improved magnetic resonance imaging (MRI) technology has led to more rapid scanning times, albeit considerably longer than typical multi-scan CT, making MRI feasible for pediatric patients and avoiding any radiation exposure; younger children may still require sedation to minimize motion artifacts during longer MRI sequences. While MRI does often reveal more detailed information about involved soft tissue, it does not usually provide much more information about IOI lesions when compared to CT , provides less information about bone changes, and is usually more expensive. B-scan ultrasonography can be used for evaluating anterior orbital lesions, but provides no information about surrounding bones, does not image the posterior one-third of the orbit, and is usually more difficult to interpret than CT and MRI.


The evaluation of patients suspected of having IOI is summarized in Table 34.3. The work-up should include a review of systems and a physical exam, as there may be systemic symptoms caused by the orbital inflammation or by a preceding upper respiratory infection; the symptoms may also herald the diagnosis of an underlying systemic autoimmune disease. Headache, vomiting, sore throat, anorexia, abdominal pain, lethargy, and weight loss have been noted in some cases. IOI alone should not cause a significant fever, although a low-grade fever may be present in some cases. Baseline laboratory studies for patients with IOI may include a complete blood cell count (CBC) with differential (cytopenias are seen in inflammation and malignancy), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), comprehensive metabolic panel (CMP), urinalysis (possible urine protein/creatinine and urine calcium/creatinine ratios), antinuclear antibody (ANA) (if positive, should be followed by evaluation for specific antibodies), rheumatoid factor (RF), angiotensin converting enzyme, anti-neutrophil cytoplasmic antibody (ANCA) [21], thyroid function studies (TSH, free T3, free T4, thyroid-stimulating immunoglobulin), EBV serologies, placement of PPD, fecal calprotectin, serum total immunoglobulin G, and/or Lyme serology in patients living in or having traveled to endemic areas. The eosinophil count may be elevated in some cases of pediatric IOI. While these studies cannot “rule in” IOI, they may be helpful in ruling out other entities. Of note, not all patients require an extended work-up, especially if the clinical and radiographic presentation is classic for IOI.

Table 34.3
Evaluation of patients with suspected orbital inflammatory disorders

Ophthalmic exam (including dilated funduscopic exam), physical exam, review of systems, medical history

Complete blood count (CBC) with differential, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), comprehensive metabolic panel (CMP), urinalysis

Orbital imaging (CT or MRI)

Additional tests may be selected if the orbital inflammation is subacute, chronic, or recurrent and a specific etiology is suspected:




Serum angiotensin converting enzyme (ACE), lysozyme

Chest X-ray or CT

Urine calcium/creatinine ratio

(Gallium scan)a

Thyroid eye disease

T3, T4

Thyroid-stimulating hormone

Thyroid-stimulating immunoglobulin, thyroid peroxidase

Granulomatosis with polyangiitis

Eosinophilic granulomatosis (Churg-Strauss syndrome)

Anti-neutrophil cytoplasmic antibody (ANCA)

If positive

 1. Anti-proteinase (pr3)

 2. Anti-myeloperoxidase (MPO)

IgG4-related disease

Serum IgG4, serum IgG, IgG4/IgG ratio

Epstein-Barr virus (usually dacryoadenitis)

Epstein-Barr nuclear antigen (EBNA)

Viral capsid antigen (VCA)-IgG and IgM

Systemic lupus erythematosus, Sjögren syndrome

Antinuclear antibody (ANA) titer, if positive:

ANA profile (dsDNA, RNP, Smith, SS-A, SS-B)

Urine protein/urine creatinine ratio

+/− anti-phospholipid antibodies

aRecent studies have questioned the utility of gallium scanning in patients with suspected sarcoidosis

The Question of Tissue Biopsy

The role of orbital biopsy in the diagnosis of IOI has been debated at length in the literature [5, 6, 16, 22]. Briefly, some experts posit that an orbital biopsy should be attempted in all patients before beginning steroid treatment of presumed IOI, provided the tissue in question is easily accessible, arguing that “inflammation” is not a diagnosis but may be a sign of a potentially dangerous underlying tissue process [6]. Others counter that a corticosteroid trial is part of a diagnostic and therapeutic protocol in patients who present in a manner typical for IOI and who have corroborating imaging studies, and that orbital exploration may expose the typical IOI patient to unnecessary surgical risk [1, 5, 15]. These experts reserve orbital biopsy for patients with an atypical presentation, for those who do not experience an immediate and sustained response to corticosteroids, and for those whose symptoms recur.

Philosophic differences aside, clinical practice typically marries axioms of both camps. Most agree that in the case of orbital myositis or an inflammatory lesion of the orbital apex, the risks of iatrogenic injury should be weighed against the benefits of histologic confirmation [23]. Similarly, advocates of biopsy argue that there is an unacceptably high incidence of malignancy in lacrimal gland masses [8, 24] and that any easily accessible involved tissue should be biopsied. In addition, any atypical presentations (subacute onset of symptoms, recurrence of symptoms on or after steroid taper, bone erosion on imaging) or a history of local or distant malignancy should prompt a biopsy.

In the pediatric population, where the specter of malignancy includes metastatic neuroblastoma, rhabdomyosarcoma, and leukemic lesions, among others (see Chap. 36), which may present in a manner similar to IOI, few would argue with the importance of tissue biopsy of accessible tissue, especially the lacrimal gland.

When performed, histologic evaluation should include consideration for malignancy, granulomas (e.g. sarcoidosis), inflammatory bowel disease and tuberculosis, vasculitis (e.g., ANCA-associated vasculitis, polyarteritis nodosa)), atypical infection (fungus, mycobacteria), and IgG4 staining. If tissue biopsy (especially of the lacrimal gland) for suspected IOI is performed, consideration should be given to debulking with or without intralesional corticosteroid injection. A recent study concluded that this may decrease recurrence of IOI [25]. If possible, systemic corticosteroid treatment should be withheld until biopsy has been performed to minimize any masking of serious pathology by corticosteroid therapy.


Treatment of IOI is usually initiated based on characteristic clinical and orbital imaging findings. A bacterial infection must be excluded if there is one or more of the following findings: pyrexia, increased white blood cell count (WBC) with neutrophilia and left shift, or CT- or MRI-documented sinusitis. One should also consider the possibility of infection or inflammation from an occult, organic foreign body in children, who frequently do not admit to a history of previous trauma. If infectious orbital cellulitis or dacryoadenitis is a possibility, it is best to obtain blood cultures and treat with broad-spectrum systemic antibiotics for 48 h (see Chap. 33, Orbital Infections) before initiating corticosteroids; of note, there is no clear evidence that corticosteroids, when used in conjunction with systemic antibiotics, worsen the course of pediatric orbital cellulitis [26].


If there is no concern for an infectious etiology, the mainstay of treatment for IOI is corticosteroids (CS). Corticosteroids inhibit the explosive inflammatory cascade of IOI at almost every level by suppressing levels of pro-inflammatory cytokines. While parenteral steroids may be used in select cases, the most common route of administration is oral. A starting dose of 1.0–1.5 mg/kg/day of prednisone is usually tapered over the following weeks to months depending on how rapidly the inflammation resolves [11]. A definite improvement should be evident within 48 h of adequate prednisone therapy, and some consider this rapid response to be diagnostic of IOI (Fig. 34.3) [27]. Others counter that patients with other inflammatory, infectious, or neoplastic entities may also demonstrate improvement on systemic CS and, therefore, a “steroid response” cannot be diagnostic of IOI [6, 22, 28]. In addition, caution should be taken in patients who have an initially good response but who cannot be easily tapered off CS therapy or if recurrence occurs after successful taper. Such cases are considered “atypical” and should prompt a review of the case, consideration of tissue biopsy, and/or further systemic work-up.


Fig. 34.3
IOI . The patient showed in Fig. 34.1 before (top) and 24 h after (bottom) initiation of oral corticosteroid therapy. Note near-complete resolution of the patient’s external signs. The patient also noted complete resolution of pain and diplopia

The use of CS over weeks to months is not without significant drawbacks. Children treated with CS may experience increased appetite, weight gain, gastritis, headache, poor sleep, and mood lability (that can in rare cases cause psychosis) [29]. Additionally, elevated blood and intraocular pressure and elevated blood sugar may be seen, although these complications are less common in the pediatric population [29, 30]. Some of the short-term side effects, especially on mood and sleep, may be mitigated by administration of CS in the morning to mimic the endogenous cortisol burst. The classic “Cushingoid appearance ” (moon facies, buffalo hump, central obesity) is due to the redistribution of fat reserves, coupled with an increased appetite. This, as well as cutaneous striae, can develop quickly in some children and may have long-term effects on self-image, especially in teenagers. Corticosteroids also have an effect on linear growth by inhibiting the synthesis of type I procollagen, which is essential for bone growth [31]. This phenomenon is especially prevalent with prolonged treatment regimens (>6 months) [29]. Fortunately, CS also inhibit closure of epiphyseal plates [29, 31]. Long-term studies of children treated with oral CS for capillary hemangioma [29] or inhaled CS [30] for asthma demonstrate that there is often a rebound in growth after CS taper, allowing children to rejoin previous growth curves and attain normal adult height.

Due to the potential of side effects related to systemic CS treatment, some clinicians suggest local intra-orbital injections of triamcinolone acetonide in cases of inflammatory masses or dacryoadenitis [32, 33]. It should be noted that this is an off-label use of the medication and carries the rare but inherent risk of intravascular embolization of particulate matter [34] and that, in children, this likely necessitates sedation, all of which limit effective access to this treatment modality. The use of other, non-particulate CS agents (e.g., dexamethasone) is not well reported.


Radiation is an effective treatment for IOI, especially in patients who are CS responsive but intolerant of CS-related side effects [27, 35]. Low doses of external beam irradiation (2000 cGy total in 200 cGy fractions) have an efficacy equivalent to CS medications in the treatment of IOI [36, 37]. Despite a recent study showing significant associations between estimated radiation doses from CT scans and the subsequent incidence of leukemia and brain tumors [38], documented complications related to orbital irradiation within this treatment dose range (i.e., cataract formation, retinal microvascular changes, keratoconjunctivitis sicca, induction of secondary carcinomas) are extremely rare [37]. However, the specter of children previously treated with external beam radiation at higher doses (5000–6000 cGy) for retinoblastoma [39] and rhabdomyosarcoma [40] looms large. In these patients, there is a marked increase in the incidence of secondary tumors within the radiation field. Additionally, the degree of bony hypoplasia and soft tissue deformities has been shown to be inversely proportional to the patient’s age at treatment and is much less severe if treated after the age of 3–4 years [41].

Other Treatment Options

Increasingly there is literature to support the use of immunomodulatory (IMT) agents in other systemic inflammatory conditions (see section “Pharmacotherapy” below), and these agents may be employed in the treatment of IOI; the guidance of a pediatric rheumatologist or oncologist is advisable.

Classification of IOI

IOI can be classified into six groups based on anatomic location and clinical presentation: anterior, diffuse, diffuse sclerosing, apical, myositic, and lacrimal [8]. Anterior, myositic, and lacrimal are the most common presentations and also usually have the best response to CS therapy.


The anterior presentation may be either acute or subacute (Fig. 34.4). Pain is usually a significant complaint. Tissue involvement usually extends no further posteriorly than the posterior aspect of the globe. Lid edema and erythema, exophthalmos, mildly decreased extraocular muscle movements, decreased visual acuity, chemosis, and diffuse bulbar conjunctival injection may be present. The most severe cases may be accompanied by iridocyclitis, especially if there are recurrent or bilateral episodes [11, 12, 42, 43]. Posterior scleritis with exudative retinal detachment may also occur (Fig. 34.5). There is usually a prompt improvement with CS therapy, although steroid-sparing agents or biologic therapy with tumor necrosis factor-alpha inhibitors (e.g., infliximab) may be necessary for long-term control.


Fig. 34.4
Anterior IOI . Axial CT (soft tissue window) demonstrates marked thickening of Tenon capsule secondary to inflammation (“tenonitis”)


Fig. 34.5
Posterior scleritis . (a) Sudden onset of left eye pain, blurred vision, and diffuse, violaceous conjunctival and episcleral injection. (b) Optical coherence tomography of the macula shows diffuse chorioretinal folds. (c) B-scan ultrasonography demonstrates marked choroidal thickening with a characteristic “T-sign”. (d) Axial CT (soft tissue window) shows diffuse thickening of the left sclera with inflammatory spillover into the bulbar conjunctiva


Diffuse IOI is much less frequent than anterior IOI. It is more likely to be subacute, remitting and progressive and to result in residual scarring. It usually causes lid edema, exophthalmos, decreased extraocular muscle movements, decreased visual acuity, chemosis, and bulbar conjunctival injection. It responds to CS therapy, but maintenance therapy may be required if it is recurrent.


Sclerosing IOI differs from diffuse IOI in several respects [8, 44]. It is more likely to present insidiously with less pain and inflammation, to be less responsive to CS therapy, and to result in fibrosis, which can cause permanent damage to the extraocular muscles, the levator muscle, and the optic nerve. Initially the fibrosis may involve only a portion of the orbit but can progress to involve the entire orbit (Fig. 34.6). Early aggressive therapy with CS, cyclophosphamide, and external radiation therapy offers the best prognosis for arresting this category of IOI [8, 44]. Medical and radiation management is typically frustratingly ineffective. Histopathologically, fibrosis overwhelms the inflammatory component, and, not surprisingly, therapy geared toward inflammation does not work. Sequential orbital debulking may provide temporary relief, and in extreme cases of progressive disease and pain, orbital exenteration may be necessary. Some experts have justifiably questioned whether sclerosing IOI is in fact a subtype of IOI or a completely separate entity of progressive idiopathic orbital fibrosis [45, 46].


Fig. 34.6
A 6-year-old girl presented with non-painful, progressive proptosis over several months. (a) External ophthalmoplegia with a distinct lack of eyelid erythema was present on exam. (b) Eventual orbital biopsy revealed fibrosis with mild inflammation. (c, d) Axial and coronal CT images demonstrate a large superolateral mass. In this case, the surrounding bone showed no change. In some cases of sclerosing pseudotumor, erosion of orbital walls may be present with extension of the process into the adjacent paranasal sinuses. (e, f) The lesion on T1-weighted, pre-contrast MRI (axial and coronal). The adjacent sinus congestion was unrelated to the fibrosing orbital process


Apical presentation is usually subacute and often recurs. Pain is often severe. Decreased vision and decreased extraocular muscle movements are likely. Exophthalmos, lid edema, chemosis, and bulbar conjunctival injection are usually mild (Fig. 34.7). Optic neuritis, apical tumors, and Tolosa-Hunt syndrome must be considered in the differential diagnosis. In rare cases, optic neuropathy may occur and progress rapidly to permanent visual loss [47].


Fig. 34.7
Orbital apical IOI . Axial, pre-contrast (left) and coronal, post-contrast T1-weighted MR images of an apical inflammatory process that presented with pain, external ophthalmoplegia, and mild optic neuropathy. Intravenous corticosteroids resulted in prompt resolution of symptoms

Tolosa-Hunt syndrome is also described as an idiopathic inflammatory condition, but is centered intracranially – posterior to the orbital apex in the cavernous sinus or posterior to the superior orbital fissure (Fig. 34.8) [48]. Of note, some experts do not classify Tolosa-Hunt syndrome as a subtype of IOI, but as a separate entity of granulomatous inflammation of the cavernous sinus and carotid siphon. Tolosa-Hunt syndrome typically presents with severe pain and external ophthalmoplegia secondary to cranial neuropathy within the cavernous sinus. Pain responds rapidly to appropriate CS doses, but the cranial neuropathy may linger for weeks to months. Tolosa-Hunt syndrome also has a propensity for recurrence and for contralateral cavernous sinus involvement. It is generally a presumptive diagnosis, since biopsy of the cavernous sinus is not without significant risk; other diagnoses which may show some response to CS therapy should be considered, including metastasis, lymphoma, meningioma, and even aneurysm.


Fig. 34.8
Presumed Tolosa-Hunt syndrome . Axial (top) and coronal (bottom) post-contrast T1-weighted MR images of a patient presenting with pain and external ophthalmoplegia but no eyelid signs. Note the enlargement and enhancement of the right cavernous sinus (arrows)

Orbital Myositis

Orbital myositis is usually acute. Diplopia is a common presenting symptom. There is usually pain on eye movement, especially when the affected muscle(s) contracts or stretches. Lid edema, chemosis, and bulbar conjunctival injection are frequent (Fig. 34.9). Visual acuity is usually not impaired. Response to CS is usually rapid and dramatic [8, 10, 11, 49]. One or more rectus or oblique muscles can be affected (Fig. 34.7) [50, 51]. The muscle enlargement typically involves the entire muscle including the tendon, which helps to differentiate it from the tendon-sparing muscle enlargement of TED [49]. However, the validity of this teaching has been questioned recently by Moembaerts [52]. The margins of the muscle may appear distinct without the irregular margins seen on CT scans of other forms of IOI. Recurrences can occur months or years later involving the same or different muscles in the same or the other orbit. The differential diagnosis includes TED, arteriovenous fistulas (e.g., direct or indirect carotid cavernous fistulas), superior ophthalmic vein thrombosis, and tumors involving extraocular muscles.


Fig. 34.9
Myositis . Injection is noted over the insertion of the left medial rectus muscle (top) in this patient with sudden onset of pain. Axial post-contrast T1-weighted MRI with fat suppression shows diffuse enlargement and enhancement of the left medial rectus muscle. Note that the tendon is relatively spared, a finding suggestive of thyroid eye disease. Recent studies have questioned the validity of using tendinous involvement or sparing as a reliable sign of specific pathologies

Lacrimal Gland (Dacryoadenitis)

Lacrimal gland involvement may be acute or subacute. Pain is not usually as severe as in the other forms of IOI. Tender, palpable enlargement of the lacrimal gland is usually present. The lid is usually more swollen temporally with an S-shaped contour deformity. Chemosis and bulbar conjunctival injection are often present, especially temporally. Vision is not usually affected. Exophthalmos is typically minimal, although the globe may be displaced inferiorly and medially (Fig. 34.10). The differential diagnosis includes viral and bacterial dacryoadenitis and tumors, as well as specific orbital inflammations (e.g., sarcoidosis, Sjögren syndrome). It is important to remember that a variety of disorders, including primary epithelial malignancies and lymphoproliferative disease, may present in an identical fashion. As already noted, because of the surgical accessibility of the lacrimal gland, some experts recommend biopsy in all cases of suspected dacryoadenitis.


Fig. 34.10
Dacryoadenitis . Acute onset of pain and swelling in the area of the left lacrimal gland. Note the enlargement and inflammation of the palpebral lobe of the gland (top). On axial CT (soft tissue window), a diffuse enlargement of the orbital lobe is also noted. The process is molding to the globe and not distorting it. The adjacent bone is intact. In some cases, spillover of inflammation onto the intraconal fat or adjacent extraocular muscles may also be seen. Note that other processes, including primary lacrimal gland epithelial malignancies and lymphoma, may present in an identical fashion and may show response, albeit temporary, to corticosteroid therapy

Specific Orbital Inflammation


Sarcoidosis is a chronic multisystem disease with the pathologic hallmark of non-caseating granulomas [53, 54] affecting the lungs, heart, skin, lymph nodes, joints, and orbit. Uveitis, dermatitis, and arthritis are the triad of early-onset childhood sarcoidosis (Blaus disease) in children younger than 5 years old, but disease in older children may parallel that in adults (pediatric -onset adult sarcoidosis) [55]. There is no specific finding or laboratory test which can conclusively diagnose sarcoidosis. The diagnosis relies, instead, on the combination of clinical history, the histologic evidence of non-caseating granulomas, and the exclusion of other possible causes [54]. Angiotensin converting enzyme [56] is produced by granuloma cells and may be elevated in up to 66% of patients diagnosed with sarcoidosis [57]; of note, the ACE level parallels the burden of disease and may be normal in localized forms of sarcoidosis. Because of the activation of macrophages, elevated 1,25-dihydroxy-vitamin D3, and/or hypercalcemia may be signs of sarcoidosis. In the United States, the disease affects blacks more frequently than whites (although there is a high incidence in patients of northern European heritage) [58]; in adults it is more common in women than in men, but this may not be the case in children.

Ophthalmic manifestations occur in up to 20% of patients with sarcoidosis, most commonly seen as uveitis, retinal vasculitis, and asymptomatic conjunctivitis, and may herald the discovery of systemic disease in 30–50% of patients [59]. However, sarcoidal findings may also be isolated, especially early in the course of the disease. Within the orbit, sarcoidosis can unilaterally or bilaterally involve the lacrimal gland, the extraocular muscles, and other soft tissues (Fig. 34.11) [60, 61]. Sarcoidal infiltration of the optic nerve and central nervous system may also occur (Fig. 34.12). The most common complaint in a large series of biopsy-proven sarcoidosis was that of a slowly progressive mass (88.5%), followed by proptosis (42%), discomfort as opposed to pain (30.8%), ptosis (27%), and restricted extraocular motility (23%) [62].


Fig. 34.11
Sarcoidosis . A 17-year-old patient presented with painless swelling of the upper eyelids. Top: On clinical exam, firm nodules were palpated across both upper lids; bilateral parotid enlargement was also noted. Middle: CT images (axial and parasagittal soft tissue windows) demonstrate nodular enlargement of both lacrimal glands extending into surrounding orbital soft tissue. Bottom left: Hilar adenopathy was identified on subsequent chest X-ray. Bottom right: Biopsy of the lacrimal gland revealed non-caseating granulomatous inflammation (white arrow, granuloma; black arrow, Langerhans giant cell). The patient’s ACE level was elevated


Fig. 34.12
Optic nerve sarcoid . A 15-year-old boy presented with progressive right visual loss over 18 months. Clinical exam revealed no light perception in the right eye with a pale optic nerve; the left optic nerve appeared normal (top). On MRI, diffuse enhancement of the optic nerve almost reaching the chiasm was observed (bottom, T1-weighted post-contrast with fat suppression). Systemic work-up, including ACE and chest CT, was normal. Optic nerve biopsy showed non-caseating granulomatous inflammation. Eighteen months later, the patient developed pulmonary symptoms. Further work-up revealed systemic sarcoidosis

Radiologically, orbital involvement can manifest as a discrete mass or as a diffuse infiltrative process. In the lacrimal gland, a well-defined homogenous enlargement and bilateral involvement are common; extraocular muscles may be involved, often in conjunction with adjacent orbital or lacrimal gland involvement [62].

Orbital inflammation in the setting of known systemic sarcoidosis should never be confused with IOI; however, there is some confusion in the ophthalmic literature regarding the diagnosis of solitary orbital sarcoid. This entity was reviewed by Mombaerts and colleagues, who presented a series of 7 patients and reviewed 30 more in the literature. All patients presented with unilateral signs of inflammation or mass effect and demonstrated non-caseating granulomas on biopsy [63]. None were found to have systemic sarcoidosis. These cases may represent “idiopathic granulomatous orbital inflammation ” [62, 63], although thorough investigation must first rule out other potential causes. Specific immunologic and microbiologic workups include tests for GPA, serologic and skin tests for fungal infections, and culture/staining for mycobacteria. The distinction between solitary orbital sarcoid and idiopathic orbital granulomatous inflammation may be academic, as both are diagnoses of exclusion and are treated in a similar manner [62].

As with most inflammatory diseases, corticosteroids (CS) are the mainstay of initial treatment for both systemic and limited sarcoidosis, but other immunotherapeutics (IMT) should be started concomitantly with the goal of weaning patients off CS within the first 2–6 months (see section “Pharmacotherapy” below). Currently, the most frequently used agents for this are methotrexate and tumor necrosis factor-alpha inhibitors [59]. Patients are kept in remission for a prolonged period of time before medications are weaned. Sarcoidosis can go into lifelong remission, although relapses occur in over 50% of patients.

Occasionally patients present with lacrimal gland sarcoidosis but do not require systemic treatment for other system involvement. In these cases, some experts suggest local injections of long-acting CS [33]. The efficacy of this therapy has not been proven in a large series of patients, and there are risks associated with periocular injections of CS (see discussion above) [34, 6466].

Granulomatosis with Polyangiitis

Granulomatosis with polyangiitis (GPA) is a necrotizing granulomatous vasculitis, usually affecting small vessels. It classically presents with constitutional symptoms and affects the respiratory tract, the sinuses, and the kidneys, although it can affect any organ system [67, 68]. It rarely occurs before adolescence. In a recently published pediatric cohort, the large majority of patients had sino-nasal and/or ear involvement along with constitutional symptoms and respiratory involvement [69]. Subglottic stenosis is not an uncommon complicating feature of pediatric disease. If untreated, the systemic variant of GPA may have a mortality of >90%. The disease may burn out in 1–2 years but may persist for longer. Although no single finding or laboratory test is diagnostic, the majority of patients with systemic GPA will have positivity for anti-neutrophil cytoplasmic antibodies (ANCA) . A child or adolescent is said to have GPA by EULAR/PRINTO/PRES 2008 criteria if at least two of the following criteria are present: (1) granulomatous inflammation on biopsy, (2) upper airway involvement, (3) laryngo-tracheo-bronchial stenosis, (4) pulmonary involvement, (5) ANCA positivity, or (6) renal involvement [70].

Ocular involvement occurs in 52–61% of patients at some point during the disease course [71], with fewer than 10% involving adnexal structures and 7–30% involving the orbit. The frequency may be lower in the pediatric population [21, 72]. Cases of GPA involving the orbit are typically part of a more limited form of the disease (also known as sino-orbital GPA) affecting the ear, nose, throat and upper airway, but sparing the kidneys [73, 74], and it is important for physicians to appreciate that few cases with disease limited to the orbit progress to systemic disease (Fig. 34.13) [75]. This “limited” form may have a chronic remitting coarse, in contrast to the fulminant “systemic” form which progresses quickly to multisystem damage and renal failure [71, 75]. Ophthalmic involvement can result from contiguous extension of respiratory system involvement in the nose and sinuses or from discrete ocular lesions. Nasal and sinus involvement can spread to the nasolacrimal duct and lacrimal sac leading to epiphora and/or dacryocystitis. Bone destruction on imaging is the rule. GPA can also lead to orbital inflammation, mimicking IOI. Discrete focal lesions not caused by contiguous spread can affect the extraocular muscles, retina, uvea, conjunctiva, lids, cornea, and sclera [72]. Ocular or facial pain was a presenting symptom in 75% of patients in one large series [73]. A third of patients with orbital GPA had associated ocular inflammation, which is less common in IOI [75]. Also in contrast to IOI, GPA often exhibits bilateral disease [73, 75].


Fig. 34.13
GPA . CT axial soft tissue window (top) and coronal bone window (bottom) of a patient with limited (sino-orbital) GPA. Note the widespread bone destruction in the paranasal sinuses and medial orbits. Scarring was also present along the medial rectus muscles, resulting in a large angle cicatricial esotropia

Radiologically, GPA can show bone destruction, a highly atypical feature for IOI (Fig. 34.13). Additionally, GPA lesions appear hyperintense on T2-weighted MRI, in contrast to many other orbital lesions, both neoplastic and inflammatory [76]. This discrepancy is thought to be due to the abundance of fibrocollagenous tissue present in the granulomatous lesions. It is important to note, however, that chronic inflammation, as seen in long-standing IOI, may also appear hyperintense on T2 images [77].

Serum ANCA is a sensitive, although not specific, indicator of ANCA-associated vasculitis (AAV) [78]. Immunofluorescence for cytoplasmic-ANCA (c-ANCA) (as opposed to perinuclear ANCA), along with antigen-specific anti-proteinase 3 (Pr3) positivity (as opposed to myeloperoxidase positivity), increases sensitivity and specificity for GPA. The antigen-specific anti-proteinase 3 Ab, often a c-ANCA pattern, is positive in 96% of patients with active generalized disease [79, 80]. It is positive in a lower percentage of patients with limited (sino-orbital) disease [81]. False-positive results of proteinase antibodies are rare in contrast to the rate seen with ANCA testing. Because atypical ANCAs can occur in inflammatory bowel disease, another granulomatous disease, it can sometimes be difficult to distinguish the two diseases. In certain patients, ANCA titers can parallel disease activity. In those in whom this is the case, ANCA titers can be useful in monitoring the response to medical therapy and may help determine relative quiescence when surgical intervention (e.g., dacryocystorhinostomy) might be safest [78].

A biopsy is recommended when feasible in all cases of GPA to confirm the diagnosis, even when c-ANCA is positive [82]. Occasionally, orbital biopsies in patients with GPA show minimal inflammation. Nasal biopsies are more likely than orbital biopsies to show the pathologic triad of vasculitis, granulomatous inflammation with giant cells, and tissue necrosis. For this reason, biopsies are often taken from multiple sites.

Children with orbital inflammation resulting from GPA should be under the care of a pediatric rheumatologist. Other than diagnostic biopsies, reconstructive orbital or lacrimal surgery should be deferred until the clinical course and/or serologic testing suggest inactivity, which can often be induced by high-dose CS; a variety of treatments are used to maintain remission (see Therapeutic discussion). While azathioprine was frequently used in the past [83], currently, rituximab is becoming the treatment of choice [8487], especially for orbital disease [88]. Many practitioners also use trimethoprim and sulfamethoxazole (co-trimoxazole) as a disease suppressant [89, 90].

Only gold members can continue reading. Log In or Register to continue

Stay updated, free articles. Join our Telegram channel

Dec 19, 2017 | Posted by in OPHTHALMOLOGY | Comments Off on Pediatric Orbital Inflammatory Disorders

Full access? Get Clinical Tree

Get Clinical Tree app for offline access