Exophthalmos

Etiology

In adults, the most common cause of unilateral and bilateral exophthalmos is thyroid-associated eye disease, such as Graves-related ophthalmopathy.

In children, orbital cellulitis is the most common cause, whereas bilateral exophthalmos is most likely due to neuroblastoma and leukemia.

Typically, exophthalmos originates from four likely etiologies:[3]

• Extension of inflammation into the orbit, e.g., thyroid-related eye disease, orbital cellulitis, sarcoidosis, granulomatosis with polyangiitis, and IgG4-related disease[4][5]
• Invasion of the orbit by new growth, e.g., space-occupying benign or malignant orbital tumors such as capillary haemangioma, neuroblastoma, neurofibromatosis, leukemia, lymphoma, mucocele, pseudotumors, and secondary metastatic deposits[6][7][8]
• Interference with the venous return from the orbit, e.g., orbital varices, carotid-cavernous fistula, cavernous sinus thrombosis[9]
• Foreign matter being forced into the orbit, e.g., due to trauma

Epidemiology

The incidence of exophthalmos may vary depending upon the underlying cause. In unilateral exophthalmos, under one-third of patients will have thyrotoxic activity.[10] Ninety percent of bilateral exophthalmos was historically a result of endocrine abnormalities.[10] The mean position of the globe, as measured using an exophthalmometer, is 16 mm.[10] There is variation between the sexes and between races.

Pathophysiology

Exophthalmos typically arises from an increase in orbital contents within the bony orbit, leading to forward displacement of the globe. The origin of the increased orbital content depends on the underlying cause. In Graves ophthalmopathy, enlargement of the extraocular muscles and expansion of the orbital adipose tissues occurs due to abnormal hyaluronic acid accumulation and edema collection into the retro-orbital space.[11] The mechanism of trauma and pathogenesis of neoplastic disease are also important factors to consider in exophthalmos.

History and Physical

The presentation may be variable, depending on the underlying cause.  Symptoms can include:[12]

• Bulging eyes - this may be measured with an exophthalmometer.
• Lid/periorbital swelling - this may be unilateral or bilateral and be associated with conjunctival chemosis or orbital cellulitis.
• Diplopia - the restriction of the extraocular muscles causes this. They may be the source of inflammation (myositis), or a growing tumor may compress them.
• Red-eye - conjunctival hyperemia increases with exophthalmos as a result of dilatation. In severe cases, there may be a secondary exposure keratopathy as a result of incomplete lid closure over the cornea.
• Ophthalmoplegia - typically in infectious conditions, inflammatory processes, or aggressive tumors.
• Reduced visual acuity

A thorough history will help establish the underlying cause. Symptoms such as heat intolerance, weight loss, change in bowel habits, and palpitations may support a diagnosis of thyrotoxicosis. There may be a history of trauma or constitutional symptoms such as weight loss that may suggest cystic or tumoral growth. The rate of onset may provide insight into its etiology. Rapid onset may suggest inflammatory disease, malignant tumors, and carotid-cavernous fistula, while gradual onset implies somewhat benign pathology. The presence of pain may commonly indicate infection (e.g., orbital cellulitis).[13] Temporary exophthalmos triggered by the Valsalva maneuver may be consistent with orbital varices.[14]

The examination should include a general examination of the patient to identify any systemic disease such as Graves' disease, leukemia, visceral neoplasm, or constitutional signs that may give rise to suspicion of malignancy. Clinicians must undertake a full eye examination, assessing a patient's extraocular movements, visual acuity, field assessment, pupil accommodation, and reflexes. Intraocular pressures, anterior segment, and fundoscopy should be performed.

Exophthalmos may be seen on examination and quantified using an exophthalmometer, whereby the extent is measured by the distance from the corneal apex to the midpoint of the anterior rim of the orbit.[10] It may be accompanied by other extraocular and systemic signs relevant to systemic causes. The clinician should remain at the same level as the patient. The white of the sclera is commonly exposed inferiorly to the iris in exophthalmos.

Evaluation

A full diagnostic workup must include a full screen of blood tests, including complete blood count (CBC), thyroid function and auto-antibody tests, renal function, and C-reactive protein. Nasal swabs and blood cultures may be warranted if severe infection is suspected e.g., orbital cellulitis.

Radiological imaging is essential for diagnostic and management purposes. Computed tomography (CT) and magnetic resonance imaging (MRI) are the gold standard modalities in evaluating the orbit or cranium for causes of severe infection, mass growth, and foreign bodies related to exophthalmos.[15] Positron emission tomography (PET) allows the assessment of metastatic disease, including leukemia, lymphoma, and metastases from secondary cancers.

As many cases may present with overlapping clinical features and may provide difficulty in confirming the diagnosis, a tissue biopsy may be necessary to ascertain a definitive answer.[4]

Proptosis or exophthalmos may be associated with other deviations of the globe, namely, hyperglobus, hypoglobus, esoglobus, or exoglobus.[16]

Treatment / Management

General

Treatment of the underlying cause is necessary for the management of exophthalmos to maintain ocular function. In the case of thyroid-associated orbitopathy and other secondary causes, effective management requires an interprofessional approach between eye specialists, primary care clinicians and, endocrinologists.[17]

Lifestyle Modifications 

Smoking cessation is paramount in the prevention and progression of thyroid eye disease.[18]

Conservative Management

Supportive therapies will provide appropriate symptomatic relief for patients while treatment of the underlying cause commences. Topical preservative-free ocular lubricants and taping eyelids should be administered to patients with dry eyes.[19] Around 66% of mild cases resolve within six months, hence supportive therapy may suffice.[19] Sunglasses and protective eyewear can be encouraged to help protect against photosensitivity and glare. Diplopia is manageable with Fresnel prism or monocular occlusion. Finally, upper eyelid retraction may be corrected with botulinum toxin injection directly into the levator palpebrae superioris.[20]

Medical Management

Moderate-to-severe thyroid orbitopathy is treated with oral and intravenous corticosteroids.[20] Inflammatory and autoimmune causes will benefit from reducing edema and orbital congestion. Chemotherapy agents may be options to reduce tumor bulk and burden.

Surgical Management[21](B3)

Surgery is indicated to remove the offending tissue, tumor, or malignant disease where appropriate. 

Orbital decompression and extraocular muscle repair have served to protect vision in severe cases of exophthalmos for decades, particularly when patients fail to respond to medical therapy.[22] The visual function has reportedly improved by up to 82% of cases.[22](B3)

Differential Diagnosis

Autoimmune, inflammatory conditions, trauma, and neoplastic disease are the most common differentials that must merit consideration in the differential diagnosis. These include thyroid-associated orbitopathy linked with Graves disease; infectious conditions such as orbital and preseptal cellulitis; vascular malformations including carotid-cavernous fistula; benign and malignant tumors including malignancy including capillary haemangioma, neuroblastoma, leukemia, lymphoma, mucocele, pseudotumors, and secondary metastatic tumors that may give rise to metastatic deposits in the orbit. Other rare differentials may include Crouzon syndrome and Apert syndrome. Periorbital fractures due to trauma may result in periorbital hemorrhage that can potentially protrude the globe.[12]

Prognosis

Early detection of the underlying cause of exophthalmos is vital for resolution. Any associated swelling, pain, or erythema will be typically self-limiting after 2 to 3 months, although this may vary from patient to patient. Thyroid-related exophthalmos may take much longer, or may not return to normal, with up to 5% of cases retaining permanent diplopia, and worsening or sustaining permanent visual impairment.

Complications

These typically are related to the underlying disease. Prolonged exposure of the cornea may result in secondary exposure keratopathy if the cornea becomes very dry, particularly at night, if there is incomplete eyelid closure. This condition may lead to chemosis and conjunctivitis. Corneal ulceration and keratitis may follow as further complications. Permanent visual disturbance such as diplopia is rare if the underlying etiology receives treatment early and swiftly. Other rare complications have also included superior limbic keratoconjunctivitis and optic atrophy.[23]