The Wills Eye Manual

Chapter 7. Orbit

7.1 Orbital Disease

This section provides a framework to evaluate a variety of orbital disorders.

Symptoms

Eyelid swelling, bulging eye(s), and double vision are common. Pain, decreased visual acuity, decreased color vision, and changes in facial sensation can occur.

Signs

Critical. Globe dystopia (e.g., proptosis/exophthalmos, hypoglobus, and hyperglobus) and restriction of ocular motility, which can be confirmed by forced duction testing (see Appendix 6, Forced Duction Test and Force Generation Test). Resistance to retropulsion of the globe is common.

Differential Diagnosis of Proptosis

 Mass effect (e.g., infiltration or displacement of soft tissues by inflammatory, neoplastic, vascular, or infectious etiologies).

 Enlarged globe (e.g., myopia). Large, myopic eyes frequently have tilted discs and peripapillary crescents, and ultrasonography (US) reveals a long axial length. Asymmetric myopia may be present as a unilateral pseudoproptosis.

 Enophthalmos of the fellow eye (e.g., after an orbital floor fracture).

 Asymmetric eyelid position: Unilateral upper and/or lower eyelid retraction, or contralateral upper eyelid ptosis.

 Physiologically shallow orbits.

Etiology

Specific signs of orbital disease are rarely diagnostic. Orbital disease can be grouped into six broad categories to help tailor the necessary workup:

1. Inflammatory: Thyroid eye disease (TED), idiopathic orbital inflammatory syndrome (IOIS), sarcoidosis, granulomatosis with polyangiitis (GPA, formerly Wegener granulomatosis), reactive inflammation from paranasal sinusitis, IgG4-related disease, etc.

2. Infectious: Orbital cellulitis, subperiosteal abscess (SPA), mucormycosis, etc.

3. Neoplastic (discrete, infiltrative, or hematologic): Typically categorized as primary (e.g., solitary fibrous tumor), secondary (e.g., extension of sinus mucocele or intracranial meningioma, etc.), or metastatic. May be benign or malignant.

NOTE: As a general rule, any patient with a history of cancer and a new orbital process should be assumed to have metastatic disease unless proven otherwise.

4. Trauma: Orbital fracture, retrobulbar hemorrhage, orbital foreign body with or without secondary infection, carotid-cavernous fistula, etc.

5. Malformation: Skeletal abnormalities, congenital/genetic syndromes, etc.

6. Vascular: Usually either congenital or acquired and categorized as primary arterial (e.g., carotid-cavernous fistula) or venous (e.g., varix). Lymphangioma may also cause proptosis from intralesional hemorrhage.

Workup

1. History: Rapid or slow onset? Pain? Ocular bruit and/or pulsation? Fever, chills, systemic symptoms, skin rash, weight change? History of malignancy, diabetes, pulmonary disease, or renal disease? Trauma? History of sinonasal congestion, epistaxis? Smoking? Up to date with health maintenance and age- appropriate screenings (e.g., mammography, prostate examination/screening)? Presence of systemic symptoms—weight loss/gain, fever, chills, night sweats, change in bowel habits, heat/cold intolerance?

2. Examination:

 Review vital signs, particularly temperature.

 Check visual acuity, size and reactivity of pupils, visual fields, color vision, and intraocular pressure. Check for pulsatility of semicircles on Goldmann tonometry.

 Check extraocular movements. Measure any ocular misalignment ([prisms or Maddox rod], see Appendix 3, Cover/Uncover and Alternate Cover Tests and 10.7, Isolated Fourth Cranial Nerve Palsy). Consider forced duction and force generation testing in select cases (see Appendix 6, Forced Duction Test and Force Generation Test).

 Check for globe dystopia. Tilt the patient’s head back and look from below ("ant's-eye view"). Measure with a Hertel exophthalmometer. Position the exophthalmometer against the lateral orbital rims, not the lateral canthi. The average value is 17 mm with the upper limit of normal about 22 to 24 mm. A difference between the two eyes of more than 2 mm is considered abnormal. Can be used in conjunction with a Valsalva maneuver if a venous malformation is suspected. In addition to classic axial exophthalmos, also look for nonaxial displacement of the globe (e.g., hypoglobus and hyperglobus).

 Test resistance to retropulsion by gently pushing each globe into the orbit with your thumbs. Feel along the orbital rim for a mass. Check the conjunctival cul-de- sacs carefully and evert the upper eyelid.

 Check trigeminal and facial nerve function. Check for preauricular and cervical adenopathy.

• Perform a dilated examination to evaluate the optic nerves (pallor and swelling), posterior pole (especially for chorioretinal folds), and peripheral retina.

3. Consider automated perimetry if compressive optic neuropathy is suspected.

4. Imaging studies: Orbital computed tomography (CT, axial, coronal, and parasagittal views) or magnetic resonance imaging (MRI) with gadolinium and fat suppression, depending on suspected etiology. Orbital B-scan US with or without color Doppler imaging is useful if the diagnosis is uncertain or when a cystic or vascular lesion is suspected. Consider optical coherence tomography (OCT) to assess optic nerve contour. See Chapter 14, Imaging Modalities in Ophthalmology.

5. Laboratory tests when appropriate: Triiodothyronine (T3), thyroxine (T4), thyroid-stimulating hormone (TSH), antithyroid autoantibodies (thyroid-stimulating immunoglobulin [TSI] and antithyroid peroxidase antibody [TPO]), angiotensin-converting enzyme (ACE), cytoplasmic staining, and perinuclear staining antineutrophil cytoplasmic antibody (cANCA and pANCA), lactate dehydrogenase (LDH), IgG/IgG4 levels, antinuclear antibody (ANA), serum protein electrophoresis (SPEP), complete blood count (CBC) with differential, blood urea nitrogen (BUN)/creatinine (especially if CT contrast or gadolinium is indicated), fasting blood sugar/hemoglobin A1c, blood cultures, etc.

6. Consider further systemic workup and additional imaging, depending on clinical suspicion and radiologic findings (e.g., metastasis, lymphoma, etc.).

7. Consider an excisional or incisional biopsy, as dictated by the working diagnosis. Fine-needle aspiration biopsy has a limited role in orbital diagnosis.

Additional workup, treatment, and follow-up vary according to the suspected diagnosis. See individual sections.

REFERENCES

Srinivasan A, Kleinberg T, Murchison AP, Bilyk JR. Serologic investigations in inflammatory orbital disease: part I. Ophthalmic Plast Reconstr Surg. 2016;32:321-328.

Srinivasan A, Kleinberg T, Murchison AP, Bilyk JR. Serologic investigations in inflammatory orbital disease: part II. Ophthalmic Plast Reconstr Surg. 2017;33:1-8.

7.2 Inflammatory Orbital Disease

7.2.1 THYROID EYE DISEASE

SYNONYMS: THYROID-RELATED ORBITOPATHY, GRAVES’ DISEASE

Ocular Symptoms

Early: Nonspecific complaints including foreign-body sensation, redness, tearing, photophobia, and morning puffiness of the eyelids. Early symptoms are often nonspecific and may mimic allergy, blepharoconjunctivitis, chronic conjunctivitis, etc. Upper eyelid retraction tends to develop early.

Late: Additional eyelid and orbital symptoms including lateral flare, prominent eyes, persistent eyelid swelling, chemosis, double vision, “pressure” behind the eyes, and decreased vision.

Signs

(See Figure 7.2.1.1.)

FIGURE 7.2.1.1 Thyroid-related orbitopathy with eyelid retraction and proptosis of the right eye.

Critical. Retraction of the upper eyelids with lateral flare (highly specific) and eyelid lag on downward gaze (von Graefe sign), lagophthalmos. Lower eyelid retraction is a very nonspecific sign and often presents as a normal finding. Unilateral or bilateral axial proptosis with variable resistance to retropulsion. When extraocular muscles are involved, elevation and abduction are commonly restricted and there is resistance on forced duction testing. Although often bilateral, unilateral or asymmetric TED is also frequently seen. Thickening of the extraocular muscles (inferior, medial, superior, and lateral, in order of frequency) without the involvement of the associated tendons may be noted on orbital imaging. Isolated enlargement of lateral rectus muscles is highly atypical of TED and requires further workup and possibly a biopsy. Isolated enlargement of the superior rectus/levator complex can occur in TED, but should be followed carefully for alternative causes, especially when upper eyelid retraction is not present.

Other. Reduced blink rate, significantly elevated IOP (especially in upgaze), injection of the blood vessels over the insertion sites of horizontal rectus muscles, superior limbic keratoconjunctivitis, superficial punctate keratopathy, or infiltrate or ulceration from exposure keratopathy, afferent pupillary defect, dyschromatopsia, optic nerve swelling/pallor, and rarely choroidal folds.

NOTE: Thickening of the extraocular muscles (EOMs) at the orbital apex can result in optic nerve compression and manifest in afferent pupillary defect, reduced color vision, visual field and visual acuity loss. Compressive optic neuropathy occurs in a minority of patients (5% to 7%) with TED, but must be ruled out in every patient at every visit. The optic neuropathy of TED almost invariably occurs in the setting of restrictive strabismus and increased resistance to retropulsion. Of note, in typical cases of compressive optic neuropathy from TED, axial proptosis is usually either absent or mild.

Systemic Signs

Hyperthyroidism is common (at least 80% of patients with TED). Symptoms include a rapid pulse, hot and dry skin, diffusely enlarged thyroid gland (goiter), weight loss, muscle wasting with proximal muscle weakness, hand tremor, pretibial dermopathy or myxedema, cardiac arrhythmias, and change in bowel habits. Some patients are hypothyroid (5% to 10%) or euthyroid (5% to 10%). Euthyroid patients should undergo thyroid function testing every 6 to 12 months; a significant proportion will develop thyroid abnormalities within 2 years. TED does not necessarily follow the associated thyroid dysfunction and may occur months to years before or after the thyroid dysfunction. The clinical progression of TED also has only a minor correlation with control of the thyroid dysfunction. A family history of thyroid dysfunction is common.

Concomitant myasthenia gravis with fluctuating double vision and ptosis may occur in a minority of patients. Always ask about bulbar symptoms (e.g., dysphagia, dysphonia, difficulty with breathing, weakness in proximal muscles, etc.) and fatigue in patients with suspected myasthenia gravis. The presence of ptosis (rather than upper eyelid retraction) or an adduction deficit in a patient with thyroid dysfunction and diplopia/external ophthalmoplegia should raise the possibility of myasthenia gravis (See 10.11, Myasthenia Gravis).

Differential Diagnosis of Upper Eyelid Retraction

 Previous eyelid surgery or trauma may produce eyelid retraction or eyelid lag.

 Severe contralateral ptosis may produce eyelid retraction because of Hering law, especially if the nonptotic eye is amblyopic.

 Oculomotor nerve palsy with aberrant regeneration: The upper eyelid may elevate with downward gaze, simulating eyelid lag (pseudo-von Graefe sign). Ocular motility may be limited, but the results of forced duction testing and orbital imaging are normal. Eyelid retraction is typically accentuated in adduction or in downgaze. See 10.6, Aberrant Regeneration of the Third Cranial Nerve.

 Parinaud syndrome: Eyelid retraction and limitation of upward gaze may accompany convergence-retraction nystagmus and mildly dilated pupils that react poorly to light with an intact near response (light-near dissociation).

Workup

1. History: Duration of symptoms? Pain? Change in vision? Known history of cancer or thyroid dysfunction? Smoker? Last mammogram, chest X-ray (especially in smokers), prostate examination/prostate-specific antigen (PSA) level?

2. Complete ocular examination to evaluate for exposure keratopathy (slit-lamp examination with fluorescein staining) and optic nerve compression (afferent pupillary defect, dyschromatopsia, optic nerve edema, automated perimetry, OCT). Extraocular motility (versions and ductions). Diplopia is measured with prisms or Maddox rod (see Appendix 3, Cover/Uncover and Alternate Cover Tests and 10.7, Isolated Fourth Cranial Nerve Palsy). Proptosis is measured with a Hertel exophthalmometer. Check for resistance to retropulsion. Check IOP in both primary and upgaze (increase in upgaze correlates with severity of inferior rectus muscle enlargement in TED). Dilated fundus examination with optic nerve assessment.

3. Imaging: CT of the orbit (axial and coronal views without contrast) is performed when the presentation is atypical (e.g., most cases of unilateral proptosis or any bilateral proptosis without upper eyelid retraction), or in the presence of severe congestive orbitopathy or optic neuropathy. CT in TED varies from patient to patient. In patients with restrictive strabismus and minimal proptosis (“myogenic variant”), imaging will show thickened EOMs without the involvement of the associated tendons and “apical crowding"—the loss of fat signal in the orbital apex because of enlarged EOMs. In patients with full or nearly full extraocular motility, severe proptosis, and exposure keratopathy (“lipogenic variant"), increased fat volume with minimal muscle involvement is typical.

4. Thyroid function tests (TFTs) (T3, T4, and TSH). These may be normal. TSI and TPO may sometimes be ordered and can be followed over time, and recent evidence suggests a correlation with disease activity. An elevated TSI and TPO may help guide the clinician toward a diagnosis of TED in atypical cases and guide treatment (see below).

5. Serum vitamin D level. Recent studies have shown that a subnormal result increases the risk of progressive orbitopathy.

6. Workup for suspected myasthenia gravis is necessary in selected cases. See 10.11, Myasthenia Gravis.

Treatment

1. Smoking cessation: All patients with TED who smoke must be explicitly told that continued tobacco use increases the risk of progression and the severity of orbitopathy. This conversation should be clearly documented in the medical record.

2. Refer the patient to a medical internist or endocrinologist for management of systemic thyroid disease, if present. If TFTs are normal, the patient’s TFTs should be checked every 6 to 12 months. Not infrequently, a euthyroid patient with TED will have an elevated TSI and/or TPO.

3. Treat exposure keratopathy with artificial tears and lubrication or by taping eyelids closed at night (see 4.5, Exposure Keratopathy). Wearing swim goggles at night may be helpful. The use of topical cyclosporine or lifitegrast drops for the treatment of ocular surface inflammation in TED is still under investigation, but is a reasonable long-term treatment option if dry eye syndrome is present.

4. Treat eyelid edema with cold compresses in the morning and head elevation at night. This management may not be very effective. Avoid diuretics.

5. Indications for orbital decompression surgery include optic neuropathy, worsening or severe exposure keratopathy despite adequate treatment, globe luxation, uncontrollably high IOP, and morbid proptosis.

6. A stepwise approach is used for surgical treatment, starting with orbital decompression (if needed), followed by strabismus surgery (for significant strabismus, if present), followed by eyelid surgery. Alteration of this sequence may lead to unpredictable results. Note that only a minority of patients with TED will need to undergo the entire surgical algorithm.

Other Treatment Modalities

• Corticosteroids: During the acute inflammatory phase, prednisone 1 mg/kg p.o. daily, tapered over 4 to 6 weeks, is a reasonable temporizing measure to improve proptosis and diplopia in preparation for orbital decompression surgery. There is evidence that the use of a 12-week course of pulsed intravenous corticosteroids (methylprednisolone 500 mg i.v. weekly for 6 weeks, followed by 250 mg i.v. weekly for 6 weeks) followed by a course of oral corticosteroids may result in better long-term control of TED with fewer systemic side effects than oral corticosteroids and is a reasonable option to offer patients in the acute phase of TED. Other experts question the long-term efficacy of this regimen. Periorbital corticosteroid injections are also used by some experts, but may be suboptimal to oral corticosteroids. Chronic systemic corticosteroids for long-term management should be avoided because of the systemic side effects. If systemic corticosteroids are used, a detailed discussion of the potential short- and long-term risks should be documented. The patient should undergo a baseline dual-energy X-ray absorptiometry bone density scan and be started on vitamin D/calcium supplements and gastric prophylaxis with a proton pump inhibitor. Close follow up with a primary care provider is also important for the management of blood sugar elevations and other side effects.

• Orbital radiation: The use and efficacy of low-dose orbital radiation in the management of TED remain controversial. It may be used as a modality in the acute inflammatory phase of TED or as a means to limit progression and provide long-term control. Radiation therapy appears to decrease the severity and progression of restrictive strabismus in patients with active TED; efficacy in managing other aspects of TED (including optic neuropathy) has not been proved definitively, but is advocated by some experts. Radiation therapy should be used with caution in patients with diabetes, as it may worsen diabetic retinopathy, and in vasculopaths, as it may increase the risk of radiation retinopathy or optic neuropathy, although neither of these risks have been proven definitively. All patients offered radiation therapy should be informed of the potential risks. If used, radiation is best performed according to strict protocols with carefully controlled dosage and shielding under the supervision of a radiation oncologist familiar with the technique. Typically, a total dose of 20 Gy is administered in 10 to 14 fractions over 2 weeks. Treatment may transiently exacerbate inflammatory changes and an oral prednisone taper may mitigate these symptoms. Improvement is often seen within a few weeks of treatment, but may take several months to attain the maximal effect.

 Selenium supplementation: Data from Europe confirm that the use of selenium supplementation (an antioxidant) reduces the severity and progression of mild-to-moderate TED. It remains unclear whether this finding is applicable in the United States, where no dietary selenium deficiency (as is present in certain European countries) exists. It is reasonable to offer this therapy to women with mild-to-moderate, active TED at a dose of 100 pg p.o. b.i.d for 6 months. Caution should be used in the use of selenium supplementation in men, especially with a family history of prostate cancer; some studies have suggested an increased risk of prostate cancer in males with high selenium levels, although this issue does not appear to have been settled conclusively.

 Vitamin D supplementation: Recent evidence suggests that vitamin D deficiency may be a risk factor for TED. Vitamin D supplementation has been recommended with the hope of decreasing the risk of TED progression.

 Biologics: Limited data are available on the use of biologic agents (e.g., rituximab, infliximab, adalimumab, etc.), with some studies showing efficacy and others finding none. Their use as primary therapy in lieu of more conventional modalities is, at present, off- label and controversial. Furthermore, there appears to be little consensus as to the most effective, specific biologic target in TED. Recently, the use of teprotumumab, a monoclonal antibody inhibitor of the insulin-like growth factor I receptor (IGF-IR) has shown promise in the management of TED. It was approved by the Food and Drug Administration (FDA) for use in TED patients in January 2020. For patients with moderate to severe TED, the drug is effective in decreasing exophthalmos and diplopia.

• Visual loss from optic neuropathy: Treat immediately with prednisone 1 mg/kg/d with close monitoring. In cases of severe visual loss, admission for pulsed intravenous therapy may be indicated. Radiation therapy may be offered for mild-to-moderate optic neuropathy, with the understanding that there is typically a lag in the treatment effect. Posterior orbital decompression surgery (for mild-to-severe optic neuropathy), either medial or lateral, is essential and usually effective in rapidly reversing or stabilizing the optic neuropathy. Anterior orbital decompression is usually ineffective in treating TED optic neuropathy. Teprotumumab has also been shown to effectively manage optic neuropathy in TED based on small series of patients.

Follow Up

1. Optic nerve compression requires immediate attention and close follow up.

2. Patients with advanced exposure keratopathy and severe proptosis also require prompt attention and close follow up.

3. Patients with minimal-to-no exposure problems and mild-to- moderate proptosis are re-evaluated every 3 to 6 months. Because of the potential risk of optic neuropathy, patients with restrictive strabismus may be followed more frequently.

4. Patients with fluctuating diplopia or ptosis should be evaluated for myasthenia gravis (see 10.11, Myasthenia Gravis).

5. All patients with TED are instructed to return immediately with any new visual problems, worsening diplopia, or significant ocular irritation. All smokers with TED must be reminded to discontinue smoking at every office visit, and appropriate referral to their primary physician for a smoking cessation program is indicated.

REFERENCES

Marcocci C, Kahaly GJ, Krassas GE, et al. Selenium and the course of mild Graves’ orbitopathy. N Engl J Med. 2011;364:1920-1931.

Heisel CJ, Riddering AL, Andrews CA, Kahana A. Serum vitamin D deficiency is an independent risk factor for thyroid eye disease. Ophthalmic Plast Reconstr Surg. 2020;36(1):17-20.

Bradley EA, Gower EW, Bradley DJ, et al. Orbital radiation for graves ophthalmopathy: a report by the American Academy of Ophthalmology. Ophthalmology. 2008;115(2):398-409.

Smith TJ, Kahaly GJ, Ezra DG, et al. Teprotumumab for thyroid-associated ophthalmopathy. N Engl J Med. 2017;376:1748-1761.

7.2.2 Idiopathic Orbital Inflammatory Syndrome

SYNONYM: INFLAMMATORY ORBITAL PSEUDOTUMOR

Symptoms

May be acute, recurrent, or chronic. An explosive, painful onset is the hallmark of IOIS, but is present in only 65% of patients; the remainder may have a more insidious and relatively painless presentation. Pain, prominent red eye, “boggy” pink eyelid edema, double vision, or decreased vision. Children may have concomitant constitutional symptoms (fever, headache, vomiting, abdominal pain, and lethargy) and bilateral or sequential presentation, neither of which is typical in adults.

Signs

Critical. Proptosis and/or ocular motility restriction, usually unilateral, typically of explosive onset. On imaging studies, soft tissue anatomy is involved in varying degrees. The EOMs are thickened in cases of myositis; involvement of the tendon may occur, but is by no means essential or pathognomonic. The sclera (in posterior scleritis), Tenon capsule (in tenonitis), orbital fat, or lacrimal gland (in dacryoadenitis) may be involved. The paranasal sinuses are usually clear.

Other. Boggy, pink eyelid erythema and edema, conjunctival injection and chemosis, lacrimal gland enlargement or a palpable orbital mass, decreased vision, uveitis, increased IOP, hyperopic shift (typically in posterior scleritis), optic nerve swelling or atrophy (uncommon), and chorioretinal folds.

NOTE: Bilateral IOIS in adults can occur, but should prompt a careful evaluation to rule out a systemic cause (e.g., sarcoidosis, GPA, IgG4-related orbitopathy, metastases [especially breast cancer], and lymphoma). Children may have bilateral disease in one- third of cases and may have associated systemic disorders.

Differential Diagnosis

 Orbital cellulitis and/or abscess.

 TED.

 Other noninfectious orbital inflammatory conditions: sarcoidosis, GPA, IgG4-related orbitopathy, amyloidosis, eosinophilic GPA, Sjogren syndrome, rheumatoid arthritis, systemic lupus erythematosus, histiocytosis, etc.

 Lymphoproliferative disease (including lymphoma).

 Primary orbital malignancy (e.g., rhabdomyosarcoma).

 Metastasis.

 Leaking dermoid cyst.

 Lymphangioma with acute hemorrhage.

 Vascular malformation, including carotid-cavernous fistula (CCF).

 Spontaneous orbital hemorrhage.

 Necrotic uveal melanoma.

Workup

See 7.1, Orbital Disease, for general orbital workup.

1. History: Previous episodes? Any other systemic symptoms or diseases? History of cancer? Smoking? Last mammogram, chest X-ray, colonoscopy, prostate examination? History of breathing problems? A careful review of systems is warranted. Fever, night sweats, and weight loss?

2. Complete ocular examination, including color vision, extraocular motility, exophthalmometry, IOP, and dilated funduscopic evaluation.

3. Vital signs, particularly temperature.

4. Imaging: Orbital CT (axial, coronal, and parasagittal views) with contrast: may show a thickened posterior sclera (the “ring sign” of 360 degrees of scleral thickening), orbital fat or lacrimal gland involvement, or thickening of the extraocular muscles (± their tendons). Bony erosion is very rare in IOIS and warrants further workup. Orbital MRI with contrast and fat suppression: May show EOM enlargement, infiltration of orbital fat, enlargement of the lacrimal gland, thickening of posterior Tenon/sclera, and enhancement along the optic nerve (perineuritis). In IOIS, the enhancement tends to “spill over” from an anatomic nidus into adjacent tissue (e.g., from EOM into surrounding orbital fat).

5. Blood tests as needed (e.g., bilateral or atypical cases): Westergren ESR, CBC with differential, ANA, ACE, cANCA, pANCA, LDH, IgG4/IgG levels, SPEP, BUN/creatinine, and fasting blood sugar/hemoglobin A1c (before instituting systemic corticosteroids). If sarcoidosis is suspected, consider chest CT which is significantly more sensitive than chest X-ray (CXR). Mammography and prostate evaluation are warranted in specific or atypical cases. Consider QuantiFERON-TB Gold testing before instituting corticosteroids in at-risk patients.

6. If possible, perform an incisional biopsy of involved orbital tissue if easily accessible with minimal morbidity before instituting corticosteroid therapy (corticosteroid therapy may mask the true diagnosis). The lacrimal gland is often involved in IOIS and is relatively easy to access surgically; strong consideration should be given to biopsy all cases of suspected inflammatory dacryoadenitis. However, a biopsy of other orbital structures (extraocular muscle and orbital apex) is typically avoided in cases of classic IOIS because of the potential surgical risks; biopsy of these structures is reserved for atypical or recurrent cases. Always be suspicious of metastatic disease in any patient with a history of cancer.

Treatment

1. Prednisone 1 to 1.2 mg/kg/d as an initial dose in adults and children, along with gastric prophylaxis (e.g., omeprazole 40 mg p.o. daily). All patients are warned about potential systemic side effects and are instructed to follow up with their primary physicians to monitor blood sugar and electrolytes.

2. Low-dose radiation therapy may be used when the patient does not respond to systemic corticosteroids, when the disease recurs as corticosteroids are tapered, or when corticosteroids pose a significant risk to the patient. Radiation therapy should only be used once orbital biopsy, if anatomically and medically feasible, has excluded other etiologies.

3. Steroid-sparing agents (e.g., methotrexate, cyclophosphamide, etc.) in cases that do not respond to or recur with corticosteroid therapy. Biopsy of affected tissue, when feasible, is indicated to rule out malignancy.

4. Biologic therapy may be considered in cases that fail other modalities. The efficacy of specific biologic agents (e.g., CD20 antibody, tumor necrosis factor-а (TNF-а) antibody, etc.) in IOIS is not known. There is evidence that IOIS is a T-cell driven process with elevated cytokines (including TNF-а); infliximab and adalimumab may be reasonable biologics to consider in recalcitrant or recurrent IOIS.

Follow Up

Re-evaluate in 1 to 2 days. Patients who respond dramatically to corticosteroids are maintained at the initial dose for 3 to 5 days, followed by a slow taper to 40 mg/d over 2 weeks, and an even slower taper below 20 mg/d, usually over several weeks. If the patient does not respond dramatically to appropriate corticosteroid doses, biopsy should be strongly considered. Recurrences of IOIS are not uncommon, especially at lower corticosteroid doses.

NOTE: IgG4-related disease is a recently described fibroinflammatory condition typified by lymphoplasmacytic infiltration of soft tissues by IgG4+ plasma cells, often with systemic involvement. Elevated serum levels of IgG4 may be present. Clinical management follows the typical algorithm of other orbital inflammations: systemic corticosteroids followed by steroid-sparing agents in chronic or recalcitrant cases. IgG4-related orbitopathy may involve any of the orbital soft tissues, but does not usually present in the explosive fashion of classic IOIS; enlargement and infiltration of sensory nerves on orbital imaging studies is a classic feature of IgG4-related orbitopathy. Definitive diagnosis requires histopathologic confirmation and IgG4 immunostaining. There is evidence from East Asia that IgG4-related disease may increase the risk of eventual lymphoma.

REFERENCES

Mombaerts I, Rose GE, Garrity JA. Orbital inflammation: biopsy first. Surv Ophthalmol. 2016;61:664-669.

Mombaerts I, Bilyk JR, Rose GE, et al. Consensus on diagnostic criteria of idiopathic orbital inflammation using a modified Delphi approach. JAMA Ophthalmol. 2017;135:769-776.

McNab AA, McKelvie P. IgG4-related ophthalmic disease. Part I: background and pathology. Ophthalmic Plast Reconstr Surg. 2015;31:83-88.

McNab AA, McKelvie P. IgG4-related ophthalmic disease. Part II: clinical aspects. Ophthalmic Plast Reconstr Surg. 2015;31:167-178.

7.3 Infectious Orbital Disease

7.3.1 ORBITAL CELLULITIS

Symptoms

Red eye, pain, blurred vision, double vision, eyelid and/or periorbital swelling, nasal congestion/discharge, sinus headache/pressure/congestion, tooth pain, infra- and/or supraorbital pain, or hypesthesia.

Signs

(See Figures 7.3.1.1 and 7.З.1.2.)

FIGURE 7.3.1.1 Orbital cellulitis.

FIGURE 7.3.1.2 CT of right orbital cellulitis showing fat stranding and right ethmoiditis.

Critical. Eyelid edema, erythema, warmth, and tenderness. Conjunctival chemosis and injection, proptosis, and restricted extraocular motility with pain on attempted eye movement are usually present. Signs of optic neuropathy (e.g., afferent pupillary defect and dyschromatopsia) may be present in severe cases.

Other. Decreased vision, retinal venous congestion, optic disc edema, purulent discharge, decreased periorbital sensation, and fever. CT scan usually shows adjacent sinusitis (typically at least an ethmoid sinusitis) and possibly a subperiosteal orbital collection.

Differential Diagnosis

See 7.1, Orbital Disease.

Etiology

 Direct extension from a paranasal sinus infection (especially ethmoiditis), focal periorbital infection (e.g., infected hordeolum, dacryoadenitis, dacryocystitis, and panophthalmitis), or dental infection.

 Sequela of orbital trauma (e.g., orbital fracture, penetrating trauma, and retained intraorbital foreign body).

 Sequela of eyelid, orbital, or paranasal sinus surgery.

 Sequela of other ocular surgery or intraocular infection (e.g., panophthalmitis) (less common).

 Vascular extension (e.g., seeding from a systemic bacteremia or locally from facial cellulitis via venous anastomoses).

 Extension from a septic cavernous sinus thrombosis.

NOTE: In cases of unsuspected retained foreign body, cellulitis may develop months after injury (see 3.12, Intraorbital Foreign Body).

Organisms

 Adult: Staphylococcus species, Streptococcus species, and Bacteroides species.

 Children: Haemophilus influenzae (rare in vaccinated children).

 Following trauma: Gram-negative rods.

 Dental abscess: Mixed, aggressive aerobes and anaerobes.

 Immunocompromised patients (diabetes, chemotherapy, and HIV infection): Fungi including those that produce zygomycosis infections (e.g., Mucor) and Aspergillus.

Workup

See 7.1, Orbital Disease, for a nonspecific orbital workup.

1. History: Trauma or surgery? Ear, nose, throat, or systemic infection? Tooth pain or recent dental abscess? Stiff neck or mental status changes? Diabetes or an immunosuppressive illness? Use of immunosuppressive agents?

2. Complete ophthalmic examination to evaluate for orbital signs including afferent pupillary defect, restriction or pain with ocular motility, proptosis, increased resistance to retropulsion, elevated IOP, decreased color vision, decreased skin sensation, or an optic nerve or fundus abnormality.

3. Check vital signs, mental status, and neck flexibility. Check for preauricular or cervical lymphadenopathy. Evaluate nasal passages for signs of eschar/fungal involvement in diabetic, acidotic, or immunocompromised patients.

4. Imaging: CT scan of the orbits and paranasal sinuses (axial, coronal, and parasagittal views, with contrast if possible) to confirm the diagnosis and to rule out a retained foreign body, orbital or SPA, paranasal sinus disease, cavernous sinus thrombosis, or intracranial extension.

5. Laboratory studies: CBC with differential and blood cultures.

6. Explore and debride any penetrating wound, if present, and obtain a Gram stain and culture of any drainage (e.g., blood and chocolate agars, Sabouraud dextrose agar, and thioglycolate broth). Obtain CT before wound exploration to rule out skull base foreign body.

7. Consult neurosurgery for suspected meningitis for management and possible lumbar puncture. If paranasal sinusitis is present, consider a consultation with otorhinolaryngology for possible surgical drainage. Consider an infectious disease consultation in atypical, severe, or unresponsive cases. If a dental source is suspected, oral maxillofacial surgery should be consulted urgently for assessment, since infections from this area tend to be aggressive, potentially vision threatening, and may spread into the cavernous sinus.

NOTE: Zygomycosis is an orbital, nasal, and sinus disease occurring in diabetic or otherwise immunocompromised patients. Typically associated with severe pain and external ophthalmoplegia. Profound visual loss may rapidly occur. Metabolic acidosis may be present. Sino-orbital zygomycosis is rapidly progressive and life threatening. See 10.10, Cavernous Sinus and Associated Syndromes (Multiple Ocular Motor Nerve Palsies).

Treatment

1. Admit the patient to the hospital and consider consult with an infectious disease specialist and otorhinolaryngologist.

2. Broad-spectrum intravenous antibiotics to cover Gram-positive, Gram-negative, and anaerobic organisms are recommended for 48 to 72 hours, followed by oral medication for at least 1 week.

The specific antibiotic agents vary.

 In patients from the community with no recent history of hospitalization, nursing home stay, or institutional stay, we currently recommend ampicillin-sulbactam 3 g i.v. q6h for adults; 300 mg/kg per day in four divided doses for children, a maximum daily dose of 12 g ampicillin-sulbactam (8 g ampicillin component);

 or

 piperacillin-tazobactam 4.5 g i.v. q8h or 3.375 g q6h for adults; 240 mg of piperacillin component/kg/day in three divided doses for children, and a maximum daily dose of 18 g piperacillin.

 In patients suspected of harboring hospital-associated methicillin-resistant Staphylococcus aureus (HA-MRSA) or in those with suspected meningitis, add concurrent intravenous vancomycin at 15 to 20 mg/kg q8-12h for adults with normal renal function and 40 to 60 mg/kg/d in three or four divided doses for children, with a maximum daily dose of 2 g. For adults who are allergic to penicillin but can tolerate cephalosporins, use vancomycin as dosed above plus: Ceftriaxone 2 g i.v. daily and metronidazole 500 mg i.v. q8h (not to exceed 4 g/d).

 For adults who are allergic to penicillin/cephalosporin, treat with a combination of a fluoroquinolone (for patients >17 years of age, moxifloxacin 400 mg i.v. daily or ciprofloxacin 400 mg i.v. q12h or levofloxacin 750 mg i.v. daily) and metronidazole 500 mg i.v. q8h.

NOTE: Antibiotic dosages may need to be reduced in the presence of renal insufficiency or failure. Peak and trough levels of vancomycin are usually monitored, and dosages are adjusted as needed. BUN and creatinine levels are monitored closely. Also, be aware that many antibiotics (especially tetracycline derivatives) may change the efficacy of warfarin and other anticoagulants. It is prudent to obtain internal medicine consultation for the management of anticoagulants while the patient is using antibiotics.

NOTE: The incidence of community-acquired methicillin-resistant S. aureus (CA-MRSA) is increasing in the United States, especially in urban areas. It is extremely difficult to clinically distinguish CA-MRSA from more conventional microbial pathogens. CA-MRSA may progress more rapidly and present with greater clinical severity than typical bacterial pathogens, but these are subjective criteria. It is prudent to cover CA-MRSA in severe cases of orbital cellulitis, in cases with a suspected skin source, in cases that have failed conventional therapy, or in areas of high CA-MRSA incidence. CA-MRSA is typically treated with tetracycline or a tetracycline derivative, trimethoprim/sulfamethoxazole, or clindamycin, although clindamycin resistance is on the rise.

 Nasal decongestant spray as needed for up to 3 days. Nasal corticosteroid spray may also be added to quicken the resolution of sinusitis.

 Erythromycin or bacitracin ointment q.i.d. for corneal exposure and chemosis if needed.

 If the orbit is tight, an optic neuropathy is present, or the IOP is severely elevated, immediate canthotomy/cantholysis may be needed. See 3.10, Traumatic Retrobulbar Hemorrhage for indications and technique.

 The use of systemic corticosteroids in the management of orbital cellulitis remains controversial. If systemic corticosteroids are considered, it is probably safest to wait 24 to 48 hours until an adequate intravenous antibiotic load has been given (three to four doses). Studies of pediatric orbital cellulitis with or without abscess found that the concomitant use of systemic corticosteroids with antibiotics shortened the length of intravenous antibiotic therapy and hospital stay.

Follow Up

Re-evaluate at least twice daily in the hospital for the first 48 hours. Severe infections may require multiple daily examinations. Clinical improvement may take 24 to 36 hours.

1. Progress is monitored by:

 Patient’s symptoms.

 Temperature and white blood cell (WBC) count.

 Visual acuity and evaluation of optic nerve function.

 Extraocular motility.

 Degree of proptosis and any displacement of the globe (significant displacement may indicate an abscess).

 C-reactive protein (CRP) has been found to be a helpful clinical marker in some studies. One study suggested initiating oral corticosteroids with antibiotic therapy at a threshold CRP of <4 mg/dL.

NOTE: If clinical deterioration is noted after an adequate antibiotic load (three to four doses), a CT scan of the orbit and brain with contrast should be repeated to look for abscess formation (see 7.3.2, Subperiosteal Abscess). If an abscess is found, surgical drainage may be required. Because radiographic findings may lag behind the clinical examination, clinical deterioration may be the only indication for surgical drainage. Other conditions that should be considered when the patient is not improving include cavernous sinus thrombosis, meningitis, resistant organism (HA-MRSA, CA-MRSA), aggressive organism (often from an undiagnosed odontogenic source), or a noninfectious etiology.

2. Evaluate the cornea for signs of exposure.

3. Check IOP.

4. Examine the retina and optic nerve for signs of posterior compression (e.g., chorioretinal folds), inflammation, or exudative retinal detachment.

5. If orbital cellulitis is clearly and consistently improving, then the regimen can be changed to oral antibiotics (depending on the culture and sensitivity results) to complete a 10- to 14-day course. We often use:

 Amoxicillin/clavulanate: 25 to 45 mg/kg/d p.o. in two divided doses for children and a maximum daily dose of 90 mg/kg/d; 875 mg p.o. q12h for adults;

 or

 Cefpodoxime: 10 mg/kg/d p.o. in two divided doses for children and a maximum daily dose of 400 mg; 200 mg p.o. q12h for adults;

 or

 If CA-MRSA is suspected, recommended oral treatment regimens include doxycycline 100 mg p.o. q12h (not in pregnant or nursing women and not in children younger than 8 years), one to two tablets trimethoprim/sulfamethoxazole 160/800 mg p.o. q12h, clindamycin 450 mg p.o. q6h, or linezolid 600 mg p.o. b.i.d. (only with approval from an infectious disease specialist, given current low resistance).

The patient is examined every few days as an outpatient until the condition resolves and instructed to return immediately with worsening signs or symptoms.

NOTE: Medication noncompliance is an extremely common reason for recurrence or failure to improve. The oral antibiotic regimen should be individualized for ease of use and affordability. Effective generic alternatives to brand name antibiotics include doxycycline and trimethoprim/sulfamethoxazole.

REFERENCES

Yen MT, Yen KG. Effect of corticosteroids in the acute management of pediatric orbital cellulitis with subperiosteal abscess. Ophthalmic Plast Reconstr Surg. 2005;21:363-366.

Davies BW, Smith JM, Hink EM, Durairaj VD. C-reactive protein as a marker for initiating steroid treatment in children with orbital cellulitis. Ophthalmic Plast Reconstr Surg. 2015;31:364-368.

7.3.2 SUBPERIOSTEAL ABSCESS

Signs and Symptoms

Similar to orbital cellulitis, though may be magnified in scale. Suspect a subperiosteal abscess (SPA) if a patient with orbital cellulitis fails to improve or deteriorates after 48 to 72 hours of intravenous antibiotics.

Differential Diagnosis

• Intraorbital abscess: Rare because the periorbita is an excellent barrier to intraorbital spread. May be seen following penetrating trauma, previous surgery, retained foreign body, extrascleral extension of endophthalmitis, extension of SPA, or from endogenous seeding. Treatment is surgical drainage and intravenous antibiotics. Drainage may be difficult because of several isolated loculations.

• Cavernous sinus thrombosis: Rare in the era of antibiotics. Most commonly seen with zygomycosis (i.e., mucormycosis) (see 10.10, Cavernous Sinus and Associated Syndromes [Multiple Ocular Motor Nerve Palsies]). In bacterial cases, the patient is usually also septic and may be obtunded and hemodynamically unstable. Dental infections have a propensity for aggressive behavior and may spread along the midfacial and skull base venous plexuses into the cavernous sinus. Prognosis is guarded in all cases. Manage with hemodynamic support (possibly in an intensive care unit), broad-spectrum antibiotics, and surgical drainage if an infectious nidus is identified (e.g., paranasal sinuses, tooth abscess, and orbit). Anticoagulation can be considered to limit the propagation of the thrombosis into the central venous sinuses.

Workup

See 7.3.1, Orbital Cellulitis, for workup. In addition:

1. Obtain CT with contrast, which allows for easier identification and extent of an abscess. In cases of suspected cavernous sinus thrombosis, discuss with the radiologist before CT, since special CT techniques and windows may help with diagnosis. MRI may also be indicated in cases of skull base spread of infection.

NOTE: All orbital cellulitis patients who do not improve after 48 to 72 hours of intravenous antibiotic therapy should undergo repeat imaging.

Treatment

TABLE 7.3.2.1

Age and Subperiosteal Abscess

Age (y)

Cultures

Need to Drain

<9

Sterile (58%) or single aerobe

No in 93%

9 to 14

Mixed aerobe and anaerobe

±

>14

Mixed, anaerobes in all

Yes

From Harris GJ. Subperiosteal abscess of the orbit: older children and adults require aggressive treatment. Ophthal Plast Reconstr Surg. 2001;17(6):395-397.

1. Microbes involved in SPA formation vary and are to a degree related to the age of the patient. The causative microbes influence response to intravenous antibiotics and the need for surgical drainage. See Table 7.3.2.1.

NOTE: These are guidelines only. All patients with SPA should be followed closely and managed by appropriate subspecialists, often with a combined approach (e.g., otorhinolaryngology). If an optic neuropathy is present or if the abscess is large, emergent drainage of the abscess is required. Adequate drainage may require orbital exploration. In children, a large SPA (>1250 mm3) with frontal sinus involvement often requires drainage. Simultaneous drainage of both the SPA and the paranasal sinuses appears to decrease the recurrence rate of SPA when compared to SPA drainage alone.

2. Leave an orbital drain in place for 24 to 48 hours to prevent abscess reformation.

3. Intracranial extension necessitates neurosurgical involvement.

4. Expect dramatic and rapid improvement after adequate drainage. Additional imaging, exploration, and drainage may be indicated if improvement does not occur rapidly.

5. Do not reimage immediately unless the patient is deteriorating postoperatively. Imaging usually lags behind clinical response by at least 48 to 72 hours.

REFERENCES

Garcia GH, Harris GJ. Criteria for nonsurgical management of subperiosteal abscess of the orbit: analysis of outcomes 1988-1998. Ophthalmology. 2000;107:1454-1458.

Todman MS, Enzer YR. Medical management versus surgical intervention of pediatric orbital cellulitis: The importance of subperiosteal abscess volume as a new criterion. Ophthalmic Plast Reconstr Surg. 2011;27:255-259.

Dewan MA, Meyer DR, Wladis EJ. Orbital cellulitis with subperiosteal abscess: demographics and management outcomes. Ophthalmic Plast Reconstr Surg. 2011;27:330-332.

7.3.3 ACUTE DACRYOADENITIS:

INFECTION/INFLAMMATION OF THE LACRIMAL GLAND

Symptoms

Unilateral pain, redness, and swelling over the outer one-third of the upper eyelid, often with tearing or discharge. Typically occurs in children and young adults.

Signs

(See Figures 7.3.3.1 and 7.3.3.2.)

FIGURE 7.3.3.1 External photograph of dacryoadenitis.

FIGURE 7.3.3.2 Hyperemic lacrimal gland of dacryoadenitis.

Critical. Erythema, swelling, and tenderness over the outer one-third of the upper eyelid. May be associated with hyperemia of the palpebral lobe of the lacrimal gland, S-shaped upper eyelid.

Other. Ipsilateral preauricular lymphadenopathy, ipsilateral conjunctival chemosis temporally, fever, and elevated WBC.

Differential Diagnosis

 Hordeolum: Tender eyelid nodule from the blocked gland. See 6.2, Chalazion/Hordeolum.

 Preseptal cellulitis: Erythema and warmth of the eyelids and the surrounding soft tissue. See 6.10, Preseptal Cellulitis.

 Orbital cellulitis: Proptosis and limitation of ocular motility often accompany eyelid erythema and swelling. See 7.3.1, Orbital Cellulitis.

 IOIS involving the lacrimal gland: May have concomitant proptosis, downward displacement of the globe, or limitation of extraocular motility. Typically afebrile with a normal WBC. Does not respond to antibiotics but improves dramatically with systemic steroids. See 7.2.2, Idiopathic Orbital Inflammatory Syndrome.

 Leaking dermoid cyst: Dermoid cysts often occur either superolaterally or superomedially. Leakage causes an intense and acute inflammatory reaction.

 Rhabdomyosarcoma: Most common pediatric orbital malignancy. Rapid presentation, but pain and erythema occur in only a minority of cases. See 7.4.1, Orbital Tumors in Children.

 Primary malignant lacrimal gland tumor or lacrimal gland metastasis: Commonly produces a displacement of the globe or proptosis. May present with an acute inflammatory clinical picture, but more often presents as a subacute process. Pain is common secondary to perineural spread along sensory nerves. Often palpable, evident on CT scan. See 7.6, Lacrimal Gland Mass/Chronic Dacryoadenitis.

 Retained foreign body, with a secondary infectious or inflammatory process. The patient may not remember any history of penetrating trauma.

Etiology

 Inflammatory, noninfectious: By far the most common. A more indolent and painless course is seen in lymphoproliferation, sarcoidosis, IgG4-related disease, etc. More acute and painful presentation in IOIS.

 Bacterial: Rare. Usually due to S. aureus, Neisseria gonorrhoeae, or streptococci.

 Viral: Seen in mumps, infectious mononucleosis, influenza, and varicella zoster. May result in severe dry eye due to lacrimal gland fibrosis. Usually bilateral.

Workup

The following is performed when an acute etiology is suspected.

When the disease does not respond to medical therapy or another etiology is being considered, see 7.6, Lacrimal Gland Mass/Chronic Dacryoadenitis.

FIGURE 7.3.3.3 CT of dacryoadenitis.

1. History: Acute or chronic? Fever? Discharge? Systemic infection or viral syndrome?

2. Palpate the eyelid and the orbital rim for a mass.

3. Evaluate the resistance of each globe to retropulsion.

4. Check for proptosis by Hertel exophthalmometry.

5. Complete ocular examination, particularly extraocular motility assessment.

6. Obtain smears and bacterial cultures of any discharge.

7. Examine the parotid glands (often enlarged in mumps, sarcoidosis, tuberculosis, lymphoma, and syphilis).

8. Perform a CT scan of the orbit (axial, coronal, and parasagittal views), preferably with contrast (see Figure 7.3.3.3). CT is preferable to MRI in the assessment of the lacrimal gland because of better detail of the adjacent bony anatomy.

9. If the patient is febrile, a CBC with differential and blood cultures are obtained.

Treatment

If the specific etiology is unclear, it is best to empirically treat the patient with systemic antibiotics (see bacterial etiology below) for 24 hours with careful clinical reassessment. The clinical response to antibiotics can guide further management and direct one toward a specific etiology.

1. Inflammatory:

 For treatment, see 7.2.2, Idiopathic Orbital Inflammatory Syndrome. Most often corticosteroid therapy is used. However, preliminary evidence suggests a role for therapeutic debulking and local corticosteroid injection at the time of diagnostic biopsy in improving outcomes and decreasing recurrence.

 Analgesic as needed.

2. Viral (e.g., mumps and infectious mononucleosis):

 Cool compresses to the area of swelling and tenderness.

 Analgesic as needed (e.g., acetaminophen 650 mg p.o. q4h p.r.n.).

NOTE: Aspirin is contraindicated in young children with a viral syndrome because of the risk of Reye’s syndrome.

3. Bacterial or infectious (but unidentified) etiology:

a. If mild to moderate:

 Amoxicillin/clavulanate: 25 to 45 mg/kg/d p.o. in two divided doses for children, a maximum daily dose of 90 mg/kg/d; 875 mg p.o. q12h for adults; or

 Cephalexin 25 to 50 mg/kg/d p.o. in two divided doses for children; 500 mg p.o. q6-12h for adults.

b. If moderate to severe, hospitalize and treat as per 7.3.1, Orbital Cellulitis.

Follow Up

Daily until improvement is confirmed. In patients who fail to respond to antibiotic therapy, judicious use of oral prednisone (see 7.2.2, Idiopathic Orbital Inflammatory Syndrome) is reasonable, as long as close follow up is maintained. Inflammatory dacryoadenitis should respond to oral corticosteroid therapy within 48 hours. Watch for signs of orbital involvement, such as decreased extraocular motility or proptosis, which requires hospital admission for i.v. antibiotic therapy and close monitoring. See 7.6, Lacrimal Gland Mass/Chronic Dacryoadenitis.

7.4 Orbital Tumors

7.4.1 ORBITAL TUMORS IN CHILDREN

Signs

Critical. Proptosis or globe displacement.

Other. See the specific etiologies for additional presenting signs. See Tables 7.4.1.1 and 7.4.1.2 for imaging characteristics.

TABLE 7.4.1.1

Childhood Orbital Lesions

TABLE 7.4.1.2

CT and MRI Characteristics of Pediatric Orbital Lesions

Differential Diagnosis

FIGURE 7.4.1.1 Hemangioma of infancy.

FIGURE 7.4.1.2 T-2-weighted MRI of orbital lymphangioma with subacute blood cyst.

• Orbital cellulitis from adjacent ethmoiditis: Most common cause of proptosis in children. It is of paramount importance to quickly rule out this etiology. See 7.3.1, Orbital Cellulitis.

 Dermoid and epidermoid cysts: Manifest clinically from birth to young adulthood and enlarge slowly. Preseptal dermoid cysts may become symptomatic in childhood and are most commonly found in the temporal upper eyelid or brow, and less often in the medial upper eyelid. The palpable, smooth mass may be mobile or fixed to the periosteum. Posterior dermoids typically become symptomatic in adulthood and may cause proptosis or globe displacement. Dermoid cyst rupture may mimic orbital cellulitis. The B-scan US, when used, reveals a cystic lesion with good transmission of echoes. Because of the cystic configuration and specific signal properties, CT and MRI are usually diagnostic. See 14.3, Magnetic Resonance Imaging.

 Hemangioma of infancy (capillary hemangioma): Seen from birth to 2 years, generally show slow progressive growth over the first 6 to 9 months with slow involution thereafter. May be observed through the eyelid as a bluish mass or be accompanied by a red hemangioma of the skin (strawberry nevus, stork bite), which blanches with pressure (see Figure 7.4.1.1). Proptosis may be exacerbated by crying. It can enlarge over 6 to 12 months, but spontaneously regresses over the following several years. Not to be confused with the unrelated cavernous venous malformation (cavernous hemangioma) of the orbit, typically seen in adults.

 Rhabdomyosarcoma: Average age of presentation is 8 to 10 years, but may occur from infancy to adulthood. May present with explosive proptosis, edema of the eyelids, a palpable eyelid lesion or subconjunctival mass, new-onset ptosis or strabismus, or a history of nosebleeds. Hallmarks are rapid onset and progression. Pain may occur in a minority of cases. Urgent biopsy and referral to a pediatric oncologist is warranted if suspected.

 Metastatic neuroblastoma: Seen during the first few years of life (usually by the age of 5 years). Abrupt presentation with unilateral or bilateral proptosis, eyelid ecchymosis, and globe displacement. The child is usually systemically ill, and 80% to 90% of patients presenting with orbital involvement already have a known history of neuroblastoma. Note that metastatic neuroblastoma may also present as an isolated Horner syndrome in a child due to metastasis to the lung apex. Prognosis decreases with age.

 Lymphangioma: Usually seen in the first 2 decades of life with a slowly progressive course but may abruptly worsen if the tumor spontaneously bleeds. Proptosis may be intermittent and exacerbated by upper respiratory tract infections. Lymphangioma may present as an atraumatic eyelid ecchymosis. Concomitant conjunctival, eyelid, or oropharyngeal lymphangiomas may be noted (a conjunctival lesion appears as a multicystic mass). MRI is often diagnostic. The B-scan US, when used, often reveals cystic spaces. See Figure 7.4.1.2.

 Optic nerve glioma (juvenile pilocytic astrocytoma): Usually first seen at the age of 2 to 6 years and is slowly progressive. The presentation includes painless axial proptosis with decreased visual acuity and a relative afferent pupillary defect. Optic nerve atrophy or swelling may be present. May be associated with neurofibromatosis (types I and II), in which case it may be bilateral. Prognosis decreases with chiasmal or hypothalamic involvement. See 13.13, Phakomatoses.

 Plexiform neurofibroma: Seen in the first decade of life and is pathognomonic for neurofibromatosis type I. Ptosis, eyelid hypertrophy, S-shaped deformity of the upper eyelid, or pulsating proptosis (from the absence of the greater sphenoid wing) may be present. Facial asymmetry and a palpable anterior orbital mass may also be evident. See 13.13, Phakomatoses.

 Leukemia (granulocytic sarcoma): Seen in the first decade of life with rapidly evolving unilateral or bilateral proptosis and, occasionally, swelling of the temporal fossa area due to a mass. Typically, granulocytic sarcoma precedes blood or bone marrow signs of leukemia (usually acute myelogenous leukemia) by several months. Any patient with a biopsy-proven granulocytic sarcoma of the orbit must be closely followed by an oncologist for leukemia development. Acute lymphoblastic leukemia can also produce unilateral or bilateral proptosis.

• Langerhans cell histiocytosis (LCH): May present in the orbit as a rapidly progressive mass with bony erosion on imaging. Three variants are encountered in the orbit: (1) multifocal, multisystem LCH (Letterer-Siwe disease) occurs in children <2 years old with an aggressive multisystem course and poor prognosis; (2) multifocal unisystem LCH (Hand-Schuller-Christian disease) occurs in children 2 to 10 years of age. The classic triad includes exophthalmos, lytic bone lesions, and diabetes insipidus from pituitary stalk infiltration; (3) unifocal LCH (eosinophilic granuloma) typically causes bony erosion in the superolateral orbit suggestive of malignancy. Occurs in older children and adults. Systemic progression occurs in only a minority of cases.

Workup

1. History: Determine the age of onset and the rate of progression. Does the proptosis vary (e.g., with crying or position)? Nosebleeds? Systemic illness? Fever? Weight loss? Recent URI? Purulent nasal discharge?

2. External examination: Look for an anterior orbital mass, a skin hemangioma, or a temporal fossa lesion. Measure any proptosis (Hertel exophthalmometer) or globe displacement. Refer to a pediatrician for abdominal examination to rule out mass or organomegaly.

3. Complete ocular examination, including visual acuity, pupillary assessment, color vision, IOP, refraction, and optic nerve evaluation. Check the conjunctival cul-de-sacs carefully.

4. Urgent imaging with either CT (axial, coronal, and parasagittal views) or MRI (with gadolinium-DTPA and fat suppression) of brain and orbits to rule out infection or neoplasia.

5. If paranasal sinus opacification is noted in the clinical setting of orbital inflammation, consider immediate systemic antibiotic therapy (see 7.3.1, Orbital Cellulitis).

6. In cases of acute onset and rapid progression with evidence of mass on imaging, an emergency incisional biopsy for frozen and permanent microscopic evaluation is indicated to rule out an aggressive malignancy (e.g., rhabdomyosarcoma).

7. Other tests as determined by the working diagnosis (usually performed in conjunction with a pediatric oncologist):

 Rhabdomyosarcoma: Physical examination (look especially for enlarged lymph nodes), chest and bone radiographs, bone marrow aspiration, lumbar puncture, and liver function studies.

 Leukemia: CBC with differential, bone marrow studies, etc.

 Neuroblastoma: Abdominal imaging (e.g., CT or MRI), urine for vanillylmandelic acid, radioiodinated metaiodobenzylguanidine scintigraphy.

 LCH: CBC with differential, comprehensive metabolic panel, serum osmolarity, and skeletal survey.

Treatment

1. Dermoid and epidermoid cysts: Complete surgical excision with the capsule intact. If the cyst ruptures, the contents can incite an acute inflammatory response.

2. Hemangioma of infancy: Observe if not causing visual obstruction, astigmatism, and amblyopia. All hemangiomas of infancy will eventually involute. In the presence of visual compromise (e.g., amblyopia and optic neuropathy), several treatment options exist:

a. Systemic B-blockers: While the exact mechanisms remain unclear, propranolol has become the preferred option in the treatment of refractory and rapidly proliferating infantile hemangiomas. Side effects of propranolol include hypoglycemia, hypotension, and bradycardia. Asthmatics and those with reactive airway disease are at risk for bronchospasm. Therefore, patients should be evaluated by a pediatrician pretreatment and monitored throughout the course of treatment. The initial dose of B-blocker is typically given in conjunction with cardiopulmonary monitoring. Note that not all lesions respond to this therapy.

b. Oral corticosteroids: Used less frequently since the introduction of B-blockers. The dose is 2 to 3 mg/kg, tapered over 6 weeks. IOP must be monitored, and patients should be placed on GI prophylaxis.

c. A local corticosteroid injection (e.g., betamethasone 6 mg/mL and triamcinolone 40 mg/mL) is seldom used. Care should be taken to avoid orbital hemorrhage and central retinal artery occlusion during injection. Skin atrophy and depigmentation are other potential complications. Note that periocular injection of triamcinolone is contraindicated by the manufacturer because of the potential risk of embolic infarction. See note in 6.2, Chalazion/Hordeolum.

d. Surgical excision: If the hemangioma is circumscribed and accessible, excision can be performed effectively and is often curative.

e. Interferon therapy: Usually reserved for large or systemic lesions that may be associated with a consumptive coagulopathy or high-output congestive heart failure (Kasabach-Merritt syndrome). There is a risk of spastic diplegia with this therapy. No longer used except in rare cases because of other viable alternatives, including propranolol.

3. Rhabdomyosarcoma: Managed by urgent biopsy and referral to a pediatric oncologist in most cases. Local radiation therapy and systemic chemotherapy are given once the diagnosis is confirmed by biopsy and the patient has been appropriately staged. Significant orbital and ocular complications can occur even with prompt and aggressive management. Overall, the long-term prognosis for orbital rhabdomyosarcoma has greatly improved over the past 50 years due to advances in chemotherapy and radiotherapy, and exenteration is no longer the standard of care. Prognosis depends on the subtype of rhabdomyosarcoma, location of the lesion (orbital lesions have the best prognosis), and stage of the disease. Note that prognosis for orbital lesions decreases with spread to adjacent anatomy (paranasal sinuses or intracranial vault).

4. Lymphangioma: Most are managed by observation. Surgical debulking is performed for a significant cosmetic deformity, ocular dysfunction (e.g., strabismus and amblyopia), or compressive optic neuropathy from acute orbital hemorrhage, but may be difficult because of the infiltrative nature of the tumor. Incidence of hemorrhage into the lesion is increased after surgery. May recur after excision. Aspiration drainage of hemorrhagic cysts (“chocolate cysts”) may temporarily improve symptoms. Sclerosing therapy has become the most frequent management option for large, cystic lesions.

5. Optic nerve glioma: Controversial. Observation, surgery, radiation, and/or chemotherapy are used variably on a case-by- case basis.

6. Leukemia: Managed by a pediatric oncologist. Systemic chemotherapy for leukemia. Some physicians administer orbital radiation therapy alone in isolated orbital lesions (chloromas, granulocytic sarcomas) when systemic leukemia cannot be confirmed on bone marrow studies. However, patients need to be monitored closely for eventual systemic involvement.

7. Metastatic neuroblastoma: Managed by a pediatric oncologist in most cases. Local radiation and systemic chemotherapy.

8. Plexiform neurofibroma: Surgical excision is reserved for patients with significant symptoms or disfigurement. The lesions tend to be vascular, infiltrative, and recurrent.

9. LCH: Therapy depends on the extent of the disease. Multisystem involvement requires chemotherapy. With unifocal involvement (eosinophilic granuloma in adults), debulking and curettage are usually curative.

Follow Up

1. Tumors with rapid onset and progression require urgent attention, with appropriate and timely referral to a pediatric oncologist when necessary.

2. Tumors that progress more slowly may be managed less urgently.

7.4.2 Orbital Tumors in Adults

Symptoms

Prominent eye, double vision, and decreased vision, may be asymptomatic.

Signs

Critical. Proptosis, pain, displacement of the globe away from the location of the tumor, orbital mass on palpation, or mass found with neuroimaging. Specific tumors may cause enophthalmos secondary to orbital fibrosis.

Other. A palpable mass, extraocular motility limitation, orbital inflammation, optic disc edema or atrophy, and choroidal folds may be present. See the individual etiologies for more specific findings. See Tables 7.4.2.1 and 7.4.2.2 for imaging characteristics.

TABLE 7.4.2.1

CT and MRI Characteristics of Selected Adult Orbital Lesions

TABLE 7.4.2.2

CT and MRI Characteristics of Select Adult Extraconal Orbital Lesions

Etiology

FIGURE 7.4.2.1 MRI of cavernous venous malformation. Note the heterogeneous contrast enhancement in two lower images.

FIGURE 7.4.2.2 T-1-weighted MRI of a large frontoethmoidal mucocele. Note extension through left orbit and anterior cranial fossa with frontal lobe compression.

• Primarily intraconal/optic nerve:

1. Cavernous venous malformation (cavernous hemangioma): Most common benign orbital mass in adults. Middle-aged women most commonly affected, with a slow onset of orbital signs. Growth may accelerate during pregnancy (see Figure 7.4.2.1).

2. Mesenchymal tumors: Orbital lesions with varying degrees of aggressive behavior. The largest group is now labeled solitary fibrous tumor (SFT) and includes fibrous histiocytoma and hemangiopericytoma. These lesions cannot be distinguished clinically or radiographically. May occur at any age. Immunohistochemical staining for STAT6 is usually diagnostic.

3. Neurilemmoma (schwannoma): Progressive, painless proptosis. Rarely associated with neurofibromatosis type II. Malignant schwannoma has been reported but is rare.

4. Neurofibroma: See 7.4.1, Orbital Tumors in Children.

5. Meningioma: Optic nerve sheath meningioma (ONSM) typically occurs in middle-aged women with painless, slowly progressive visual loss, often with mild proptosis. An afferent pupillary defect may be present. Ophthalmoscopy can reveal optic nerve swelling, optic atrophy, or abnormal collateral vessels around the optic nerve head (optociliary shunts).

6. Other optic nerve lesions: Optic nerve glioma, optic nerve sarcoid, malignant optic nerve glioma of adulthood (MOGA). The second most common lesion of the optic nerve (excluding optic neuritis) after ONSM is optic nerve sarcoid, which may be difficult to distinguish from ONSM clinically and radiologically. The ACE level may be normal in cases of isolated optic nerve sarcoid. MOGA is a rapidly progressive optic nerve lesion of the elderly akin to glioblastoma multiforme; it carries a poor prognosis and is often misdiagnosed as a "progressive NAION."

7. Lymphangioma: Usually discovered in childhood. See 7.4.1, Orbital Tumors in Children.

 Primarily extraconal:

1. Mucocele: Often presents with a frontal headache and a history of chronic sinusitis or sinus trauma. Usually located nasally or superonasally, emanating from the frontal and ethmoid sinuses. See Figure 7.4.2.2.

2. Localized neurofibroma: Occurs in young- to middle-aged adults with the slow development of orbital signs. Eyelid infiltration results in an S-shaped upper eyelid. Some have neurofibromatosis type I, but most do not.

3. SPA or spontaneous hematoma: See 7.3.2, Subperiosteal Abscess.

4. Dermoid cyst: See 7.4.1, Orbital Tumors in Children.

5. Others: Tumors of the lacrimal gland (pleomorphic adenoma [well circumscribed], adenoid cystic carcinoma [ACC] [variably circumscribed with adjacent bone destruction]), sphenoid wing meningioma (commonly occurring in middle-aged females and a cause of compressive optic neuropathy), secondary tumors extending from the brain or paranasal sinuses, primary osseous tumors, and vascular lesions (e.g., varix and arteriovenous malformation including CCF).

 Intraconal or extraconal:

1. Lymphoproliferative disease (lymphoid hyperplasia and lymphoma): More commonly extraconal. About 50% are well circumscribed on imaging, and 50% are infiltrative. Ocular adnexal lymphoma is typically of the non-Hodgkin B-cell type (NHL), and about 75% to 85% follow an indolent course (extranodal marginal zone lymphoma [EMZL] or mucosa-associated lymphoid tissue lymphoma, grade I or II follicular cell lymphoma, and chronic lymphocytic leukemia [small cell lymphoma]). The remainder are aggressive lesions (diffuse large B-cell lymphoma and mantle cell lymphoma, among others). May occur at any adult age; orbital NHL is rare in children. Slow onset and progression unless there is an aggressive subtype. Pain may occur in up to 25% of orbital NHL. Typically develops superiorly in the anterior aspect of the orbit, with about 50% occurring in the lacrimal gland. May be accompanied by a subconjunctival salmon-colored lesion. Most orbital NHL (especially if indolent subtype) occurs without evidence of systemic lymphoma (Stage IE). Orbital NHL may be confused with IOIS, especially when it presents more acutely with pain. Note that NHL frequently responds dramatically to systemic corticosteroids, as does IOIS.

2. Metastases: Usually occurs in middle-aged to elderly people with a variable onset of orbital signs. Common primary sources include the breast (most common in women), lung (most common in men), and genitourinary tract (especially prostate). Twenty percent of orbital breast cancer metastases are bilateral and frequently involve extraocular muscles. Enophthalmos (not proptosis) may be seen with scirrhous breast carcinoma. Metastatic prostate adenocarcinoma has a propensity for bone and often involves the zygoma or greater sphenoid wing. Note that uveal metastases are far more common than orbital lesions by a 10 to 1 ratio.

3. Others: Mesenchymal tumors and other malignancies.

Workup

1. History: Determine the age of onset and rate of progression. Headache or chronic sinusitis? History of cancer? Trauma (e.g., mucocele, hematocele, orbital foreign body, or ruptured dermoid)? Classic lymphoma symptoms including fever, night sweats, or unintentional weight loss.

2. Complete ocular examination, particularly visual acuity, pupillary response, ocular motility, dyschromatopsia testing, an estimate of globe displacement and proptosis (Hertel exophthalmometer), IOP, optic nerve evaluation, and automated perimetry of each eye if concerned about an optic neuropathy. Examine conjunctival surface and cul-de-sacs carefully for salmon patches if lymphoma is suspected.

3. CT (axial, coronal, and parasagittal views) of the orbit and brain or orbital MRI with fat suppression/gadolinium, depending on suspected etiology and age. See 14.2, Computed Tomography and 14.3, Magnetic Resonance Imaging.

4. Orbital US with color Doppler imaging as needed to define the vascularity of the lesion. Conventional B-scan has a limited role in the diagnosis of orbital pathology because of the availability and resolution of CT and MRI, but may provide some data on anterior orbital lesions.

5. When a metastasis is suspected and the primary tumor is unknown, the following should be performed:

 Incisional biopsy to confirm the diagnosis, with estrogen receptor assay if breast adenocarcinoma is suspected.

 Breast examination and palpation of axillary lymph nodes by the primary physician.

 Medical workup (e.g., chest imaging, mammogram, prostate examination, PSA testing, and colonoscopy).

 If the patient has a known history of metastatic cancer and is either a poor surgical candidate or has an orbital lesion that is difficult to access, empiric therapy for the orbital metastasis is a reasonable option.

6. If lymphoproliferative disease (lymphoma or lymphoid hyperplasia) is suspected, a biopsy for definitive diagnosis is indicated. Include adequate fixed tissue (for permanent sectioning and immunohistochemistry) and fresh tissue (for flow cytometry). If lymphoproliferative disease is confirmed, the systemic workup is almost identical for polyclonal (lymphoid hyperplasia) and monoclonal (lymphoma) lesions (e.g., CBC with differential, serum protein electrophoresis, lactate dehydrogenase, and whole-body imaging [CT/MRI or positron emission tomography/CT]). Based on recent data, bone marrow biopsy is indicated in all cases of orbital lymphoma, even indolent subtypes. Close surveillance with serial clinical examination and systemic imaging is indicated over several years in all patients with lymphoproliferative disease, regardless of clonality. A significant percentage of patients initially diagnosed with orbital lymphoid hyperplasia will eventually develop systemic lymphoma.

Treatment

1. Metastatic disease: Systemic chemotherapy as required for the primary malignancy. Radiation therapy is often used for palliation of the orbital mass; high-dose radiation therapy may result in ocular and optic nerve damage. Hormonal therapy may be indicated in certain cases (e.g., breast and prostate adenocarcinoma).

2. Well-circumscribed lesions: Complete surgical excision is performed when there is compromised visual function, diplopia, rapid growth, or high suspicion of malignancy. Excision for cosmesis can be offered if the patient is willing to accept the surgical risks. An asymptomatic patient can be followed every 6 to 12 months with serial examinations and imaging. Progression of symptoms and rapidly increasing size on serial imaging are indications for exploration and biopsy/excision.

3. Mucocele: Systemic antibiotics (e.g., ampicillin/sulbactam 3 g i.v. q6h) followed by surgical drainage of the mucocele, usually by transnasal endoscopic technique. Orbitotomy for excision is usually unnecessary and contraindicated in most cases as disruption of the mucocele’s mucosal lining may lead to recurrent, loculated lesions.

4. Lymphoid tumors: Lymphoid hyperplasia and indolent lymphoma without systemic involvement are treated almost identically. With few exceptions, orbital lymphoproliferations respond dramatically to relatively low doses of radiation (~ 24 Gy); ocular and optic nerve complications are therefore less common than with other malignancies. Systemic lymphoma or localized aggressive lymphoma are treated with chemotherapy and in many cases with biologics (e.g., rituximab). The vast majority of orbital lymphoma is of B-cell origin and 50% to 60% are EMZL. In older individuals with few symptoms and indolent lesions, more conservative measures may be indicated, including observation alone or brief courses of corticosteroids. To date, there is no clear role for the use of systemic antibiotics in the treatment of orbital lymphoproliferative disease except possibly in certain geographic locations. There is also no clear evidence that orbital EMZL is in any way related to Helicobacter pylori- associated gastric EMZL. Remember that the specific subtype of NHL (and therefore level of aggressiveness) and stage of the disease define the ultimate treatment.

5. ONSM: The diagnosis is usually based on slow progression and typical MRI findings. MRI with gadolinium is the preferred imaging modality. CT is occasionally helpful in demonstrating intralesional calcifications. Stereotactic radiation therapy is usually indicated when the tumor is growing and causing significant visual loss. Otherwise, the patient may be followed every 3 to 6 months with serial clinical examinations and imaging studies as needed. Recent studies have shown the significant efficacy of stereotactic radiotherapy in decreasing tumor growth and in visual preservation. Stereotactic radiotherapy is not equivalent to gamma knife therapy (“radiosurgery”). Empiric stereotactic radiotherapy (i.e., without confirmatory biopsy) is a reasonable treatment option, but is reserved for typical cases of ONSM. Atypical or rapidly progressive lesions still require biopsy.

6. Localized neurofibroma: Surgical removal is performed for symptomatic and enlarging tumors. Excision may be difficult and incomplete in infiltrating neurofibromas.

7. Neurilemmoma: Same as for cavernous venous malformation (see above).

8. Mesenchymal tumors (usually SFT): Complete excision when possible. The lesion may be fixed to the surrounding normal anatomy and abut critical structures. In such cases, debulking is reasonable, with long-term follow up and serial imaging to rule out aggressive recurrence or potential malignant transformation. SFT is notoriously difficult to prognosticate. Some lesions will behave in an indolent fashion, while others may present with aggressive recurrence, regional extraorbital extension, or systemic spread.

Follow Up

1. In cases of isolated lesions that can be completely excised (e.g., cavernous venous malformation), routine ophthalmologic follow up is all that is necessary.

2. Other etiologies require long-term follow up at variable intervals.

3. Metastatic disease requires timely workup and management.

REFERENCES

Olsen TG, Heegaard S. Orbital lymphoma. Surv Ophthalmol. 2019;64:45-66.

Olsen TG, Holm F, Mikkelsen LH, et al. Orbital lymphoma: an international multicenter retrospective study. Am J Ophthalmol. 2019;199:44-57.

Rose GE, Gore SK, Plowman NP. Cranio-orbital resection does not appear to improve survival of patients with lacrimal gland carcinoma. Ophthalmic Plast Reconstr Surg. 2019;35:77-84.

NOTE: See 7.6, Lacrimal Gland Mass/Chronic Dacryoadenitis, especially if the mass is in the outer one-third of the upper eyelid, and see 7.4.1, Orbital Tumors in Children.

7.5 Traumatic Orbital Disease

ORBITAL BLOWOUT FRACTURE

(See 3.9, Orbital Blowout Fracture.)

TRAUMATIC RETROBULBAR HEMORRHAGE

(See 3.10, Traumatic Retrobulbar Hemorrhage.)

7.6 Lacrimal Gland Mass/Chronic Dacryoadenitis

Symptoms

Persistent or progressive swelling of the outer one-third of the upper eyelid. Pain or double vision may be present.

Signs

Critical. Chronic eyelid swelling, predominantly in the outer one- third of the upper eyelid, with or without proptosis and displacement of the globe inferiorly and medially. Pain may be present, especially in cases of acute IOIS of the lacrimal gland. Erythema is less common. A dull, aching pain over the forehead or along the temple is an ominous sign, suggestive of malignancy.

Other. A palpable mass may be present in the outer one-third of the upper eyelid. Extraocular motility may be restricted. May have conjunctival injection.

Etiology

FIGURE 7.6.1 CT and MRI of lesions involving or near the lacrimal gland. A: Pleomorphic adenoma with smooth, pressure induced changes in the lacrimal gland fossa (arrows). B: Adenoid cystic carcinoma with bone destruction (arrows) and intralesional calcifications. C: Lymphoma involving the lacrimal gland with molding to the globe. D: Dermoid cyst arising from the frontoethmoidal suture.

 Sarcoidosis: May be bilateral. Typically painless. May have concomitant lung, skin, or renal disease. Lymphadenopathy, parotid gland enlargement, or seventh cranial nerve palsy may be present. Of note, intraocular involvement is uncommon in patients with adnexal sarcoidal inflammation, and vice versa. More common in Americans of African descent, West Africans, and Northern Europeans.

 IOIS: See 7.2.2, Idiopathic Orbital Inflammatory Syndrome. Chronic, painless lacrimal gland enlargement is possible, but atypical for IOIS.

 IgG4-related dacryoadenitis. See Note in 7.2.2, IgG4-Related Orbitopathy.

 Infectious: Enlarged palpebral lobe with surrounding conjunctival injection. Purulent discharge with bacterial dacryoadenitis, which is much less common than noninfectious dacryoadenitis. Bilateral lacrimal gland enlargement may be seen in patients with viral illnesses. CT scan may show fat stranding, abscess.

 Benign mixed tumor (pleomorphic adenoma): Slowly progressive, painless proptosis or inferomedial displacement of the globe in middle-aged adults. Usually involves the orbital lobe of the lacrimal gland. CT may show a well-circumscribed mass with pressure-induced remodeling and enlargement of the lacrimal gland fossa. No true bony erosion occurs (Figure 7.6.1A).

 Lymphoproliferative tumor: Slowly progressive proptosis and globe displacement in an adult. May have a pink “salmon-patch” area of subconjunctival extension. CT usually shows a lacrimal gland lesion that conforms to the native anatomy and is well circumscribed. Indolent forms spare the bone, but bony erosion may be seen in aggressive histopathology (e.g., diffuse large B- cell and mantle cell lymphoma) (Figure 7.6.1C).

 ACC: Subacute onset of pain over 1 to 3 months, proptosis, and diplopia, with variable progression. Globe displacement, ptosis, and a motility disturbance are common. This malignant lesion often exhibits perineural invasion, resulting in pain along the temple or forehead and intracranial extension. CT shows an irregular mass, often with bony erosion (Figure 7.6.1B).

 Malignant mixed epithelial tumor (pleomorphic adenocarcinoma): Occurs primarily in elderly patients, acutely producing pain and progressing rapidly. May develop primarily or secondarily within a long-standing benign mixed epithelial tumor (“carcinoma ex pleomorphic adenoma”), or incompletely resected benign mixed tumor. CT findings are similar to those for ACC.

 Lacrimal gland cyst (dacryops): Usually an asymptomatic mass that may fluctuate in size. Typically occurs in a young adult or middle-aged patient.

 Others (may not involve the lacrimal gland, but occur superolaterally in the area of the lacrimal gland and fossa): GPA (formerly Wegener granulomatosis), tuberculosis, leukemia, mumps, mononucleosis, syphilis (exceedingly rare), mucoepidermoid carcinoma, plasmacytoma/multiple myeloma, eosinophilic granuloma, metastasis (especially prostate adenocarcinoma), and dermoid cyst (Figure 7.6.1D) (see Tables 7.4.1.2 and 14.3.2).

NOTE: Primary, epithelial neoplasms are almost always unilateral; inflammatory disease may be bilateral. Lymphoma is more commonly unilateral, but may be bilateral.

Workup

1. History: Determine the duration of the abnormality and rate of progression. Associated pain, tenderness, or double vision? Weakness, weight loss, fever, or other signs of systemic malignancy? Breathing difficulty, skin rash, or history of uveitis (sarcoidosis)? Any known medical problems? History of lacrimal gland biopsy or surgery?

2. Complete ocular examination: Specifically look for keratic precipitates, iris nodules, posterior synechiae, and old retinal periphlebitis from sarcoidosis. As noted, intraocular sarcoidosis is uncommon in patients with ocular adnexal sarcoidosis, but may occur.

3. Orbital CT (axial, coronal, and parasagittal views). MRI is rarely required unless an intracranial extension is suspected. CT is helpful in defining bony anatomy and abnormality.

4. Consider a chest CT, which may diagnose sarcoidosis, primary malignancy, lymphoproliferative disease, metastatic disease, and, rarely, tuberculosis.

5. Consider CBC with differential, ACE, cANCA, pANCA, SPEP, LDH, IgG4/IgG levels, and purified protein derivative (PPD) or interferon-gamma release assay (IGRA) (e.g., QuantiFERON-TB Gold) if clinical history suggests a specific etiology. In most cases, ACE and LDH suffice.

6. Lacrimal gland biopsy (see Note below) is indicated when a malignant tumor is suspected, or if the diagnosis is uncertain. If possible, avoid treatment with corticosteroids until a biopsy is obtained.

7. Systemic workup by an internist or hematologist/oncologist when lymphoma or other blood dyscrasia is confirmed (e.g., abdominal and head CT scan, PET/CT scan, possible bone marrow biopsy).

NOTE: Do not perform an incisional biopsy on lesions thought to be a benign mixed tumor (pleomorphic adenoma) or dermoid cyst. Incomplete excision of a pleomorphic adenoma may lead to a recurrence with or without malignant transformation. Rupture of a dermoid cyst may lead to a severe inflammatory reaction. These two lesions should be completely excised without violating the capsule or pseudocapsule.

NOTE: If ACC is suspected, some experts recommend avoiding large, debulking biopsies for the preservation of the lacrimal artery. A recent study on the treatment of ACC with an intra-arterial chemotherapeutic protocol concluded that efficacy is compromised if the lacrimal artery is not intact. To avoid iatrogenic injury to the artery, perform an anterior biopsy to confirm the diagnosis of ACC. Other experts do not utilize intraarterial chemotherapy and proceed with complete gross excision of the tumor and obviously involved bone in anticipation of adjunctive radiation therapy.

Treatment

1. Sarcoidosis: Systemic corticosteroids or low-dose antimetabolite therapy. See 12.6, Sarcoidosis.

2. IOIS: Systemic corticosteroids. See 7.2.2, Idiopathic Orbital Inflammatory Syndrome.

3. IgG4-related disease: Systemic corticosteroid therapy or low-dose antimetabolite therapy. Biologic therapy may also be used.

4. Benign mixed epithelial tumor (pleomorphic adenoma): Complete surgical removal.

5. Dermoid cyst: Complete surgical removal.

6. Lymphoma confined to the lacrimal gland: Depends on the subtype of lymphoma. Indolent lesions respond well to radiation therapy alone. Aggressive lesions, even when isolated, typically necessitate systemic chemotherapy, including biologic agents (e.g., rituximab). See 7.4.2, Orbital Tumors in Adults.

7. ACC: Consider pretreatment with intra-arterial cisplatinum, followed by wide excision. Orbital exenteration and craniectomy are used less frequently, especially in smaller lesions, since there appears to be no prognostic advantage over more localized excision followed by radiotherapy. Adjunctive radiation is recommended in all patients, possibly with systemic chemotherapy. Proton beam radiotherapy is offered by some centers, but, to date, there is no proven benefit over conventional stereotactic radiotherapy. Regardless of the treatment regimen, the prognosis is guarded and recurrence is the rule. There is no clear evidence that any specific treatment regimen improves survival. Survival appears to be most dependent on the specific tumor subtype (basaloid or nonbasaloid) and possibly initial tumor size.

8. Malignant mixed epithelial tumor: Similar as for ACC.

9. Lacrimal gland cyst: Excise if symptomatic.

Follow Up

Depends on the specific cause.

7.7 Miscellaneous Orbital Diseases

1. Intracranial disease. Extension of intracranial tumors, usually frontal lobe or sphenoid wing meningiomas, may present with proptosis in addition to cranial neuropathy and decreased vision. Imaging, preferably with MRI, is indicated.

2. Cavernous sinus arteriovenous fistula (AVF) (e.g., carotid- cavernous or dural sinus fistula): AVF is either spontaneous, indirect (usually in older patients, Barrow type B-D) or posttraumatic, direct (in younger patients, Barrow type A). A bruit is sometimes heard by the patient and may be detected if ocular auscultation is performed. Pulsating proptosis, arterialized “corkscrew” conjunctival vessels, increased IOP, retinal venous congestion, and chemosis may be present. May mimic an orbital disease, including TED and IOIS. In the early stages, often misdiagnosed as conjunctivitis, asymmetric glaucoma, etc. CT scan reveals enlarged superior ophthalmic vein(s), sometimes accompanied by enlarged extraocular muscles. An orbital color Doppler US shows reversed, arterialized flow in the superior ophthalmic vein(s). MRA or CTA may reveal AVF but a definitive diagnosis usually requires cerebral arteriography. Evidence of posterior cortical venous outflow on arteriography increases the risk of hemorrhagic stroke. Of note, posterior cortical venous outflow is more common in patients with bilateral orbital signs, but is seen in 10% of patients with unilateral presentation. Also remember that arteriography must be performed on both cerebral hemispheres and include the internal carotid, external carotid, and basilar arteries (“six vessel angio"). The cavernous sinuses are connected by the circular sinus and, on occasion, a carotid- cavernous fistula manifests clinically in the contralateral orbit.

3. Septic cavernous sinus thrombosis: Orbital cellulitis signs, plus dilated and sluggish pupils as well as palsies of the third, fourth, fifth, and/or sixth cranial nerves out of proportion to the degree of orbital edema. Decreasing level of consciousness, nausea, vomiting, and fevers can occur. May be bilateral with rapid progression. See 7.3.1, Orbital Cellulitis.

4. Orbital vasculitis (e.g., GPA and polyarteritis nodosa): Systemic signs and symptoms of vasculitis (especially sinus, renal, pulmonary, and skin disease), fever, markedly increased ESR, and positive cANCA or pANCA. Of note, cANCA may be normal in two-third of patients with the limited sino-orbital variant of GPA.

5. Varix: A large, dilated vein in the orbit that produces proptosis when it fills and dilates (e.g., during a Valsalva maneuver or with the head in a dependent position). When the vein is not engorged, the proptosis disappears. CT demonstrates the dilated vein if an enhanced scan is performed during a Valsalva maneuver. Calcification may be seen in long-standing lesions.

6. Poorly understood processes:

 Tolosa-Hunt syndrome (THS): NOT equivalent to orbital apical IOIS. Histopathologically, a granulomatous inflammation of the orbital apex and/or carotid siphon within the cavernous sinus. Presents with acute pain, cranial neuropathy, and sometimes proptosis. A diagnosis of exclusion. Difficult to diagnose with CT. MRI shows isolated, ipsilateral enlargement of the cavernous sinus. Usually sensitive to corticosteroid therapy, but pain typically responds much more quickly than external ophthalmoplegia, which may take weeks to resolve. Because confirmatory biopsy is usually not feasible, every patient with presumed THS must be followed long-term, even after rapid response to corticosteroids, to rule out other etiologies. Repeat imaging is usually indicated several months after the initial event to rule out progression. Presumed THS recurs in about one-third of patients. Remember that other significant pathologies, including sarcoidosis, lymphoma, metastasis, and even aneurysm may show a temporary response to corticosteroids.

 Sclerosing orbital pseudotumor: Likely not a true orbital inflammation or a subtype of IOIS. May be a form of idiopathic multifocal sclerosis. Presents with chronic pain, external ophthalmoplegia, and possibly optic neuropathy. Diagnosis requires biopsy. Histopathology shows wide swaths of monotonous fibrous tissue interspersed with mild inflammation. Treatment is difficult and may necessitate antimetabolite therapy, debulking, and in severe cases, exenteration.

 Orbital amyloid: May be primary (isolated) or secondary to systemic disease. All patients require a systemic workup, including a cardiology consult to rule out cardiomyopathy. Diagnosis is made by judicious orbital biopsy (this lesion is highly vascular and hemostasis is often difficult to obtain). Treatment is highly variable.