Graves' Ophthalmopathy (See Also Chapter 15)
Graves' ophthalmopathy is a syndrome of clinical and imaging abnormalities caused by deposition of mucopolysaccharides and infiltration with chronic inflammatory cells of the orbital tissues, particularly the extraocular muscles. It usually occurs in association with autoimmune hyperthyroidism (Graves' disease), but exactly the same disease process can occur in association with autoimmune hypothyroidism (Hashimoto's thyroiditis); thyroid dysfunction due to amiodarone; thyroid antibodies (antimicrosomal (thyroperoxidase) or antithyroglobulin antibodies, or thyroid-simulating immunoglobulins) without thyroid dysfunction; and occasionally no clinical or laboratory evidence of thyroid dysfunction and no thyroid antibodies, even on long-term follow-up. It is thought to be an autoimmune disease but which antigens and antibodies are important in its pathogenesis remains uncertain. It is associated with other autoimmune diseases, including myasthenia gravis. It is exacerbated by cigarette smoking and radioiodine therapy. (Graves' ophthalmopathy or orbitopathy, dysthyroid ophthalmopathy or orbitopathy, and (dys)thyroid eye disease or orbital disease are interchangeable terms.)
Some degree of ophthalmopathy, usually mild and typically including upper eyelid retraction, occurs in a high percentage of hyperthyroid patients. Severe ophthalmopathy with marked proptosis and restricted motility occurs in about 5% of cases of Graves' disease (Figure 13–3).
Graves' ophthalmopathy is the most common cause of unilateral or bilateral proptosis in adults or children. The accompanying upper eyelid retraction, manifesting as disproportionately greater exposure of sclera superiorly than inferiorly, and lid lag, manifesting as impaired descent of the upper eyelid on downward gaze, distinguishes it from other causes of proptosis.
Ocular surface discomfort is very common in all stages of the disease, in some cases due to superior limbic keratoconjunctivitis (see Chapter 5). Incomplete eyelid closure (lagophthalmos) results from proptosis and lid retraction, and corneal exposure may be present even in mild cases. Ptosis in association with thyroid ophthalmopathy is usually due to coexistent myasthenia gravis, which may also contribute to ocular motility disturbance.
The extraocular muscle involvement of thyroid ophthalmopathy begins with lymphocytic infiltration and edema of the rectus muscles, typically the inferior and medial recti. The inflamed muscles may become fibrotic and permanently restricted. Diplopia usually begins in the upper field of gaze. All extraocular muscles may eventually be involved, and there may be no position of gaze free of diplopia. Tethering of the inferior recti results in elevation of intraocular pressure on upgaze, or in severe cases even on looking straight ahead.
If the extraocular muscles become markedly enlarged (Figure 13–4), there may be compression of the optic nerve at the orbital apex, not necessarily accompanied by significant proptosis. Early signs include an afferent pupillary defect and impairment of color vision, followed by reduction of visual acuity. Blindness is liable to occur if compression is unrelieved.
CT scan of Graves' ophthalmopathy. A: Axial section showing markedly enlarged medial recti and left lateral rectus (arrows) and distortion of right optic nerve (arrowhead). B: Coronal section showing optic nerves (arrowheads) and markedly enlarged medial recti and left inferior rectus (arrows).
Management should be multidisciplinary. An endocrinologist should manage the thyroid status, optimal control being crucial to ameliorating the orbital disease. If hyperthyroidism cannot be controlled by drug therapy, thyroid surgery is preferable to radioiodine therapy. Whether thyroid surgery improves ophthalmopathy is uncertain. Radioidone therapy is relatively contraindicated and prophylactic steroid therapy needs to be considered if it needs to be administered. Cigarette smoking should be discouraged.
Ocular surface problems, including exposure keratitis, can usually be controlled with topical lubricants. Compressive optic neuropathy, or proptosis with severe exposure keratitis uncontrolled by lubricants, requires emergency treatment, initially with high-dose systemic steroids (oral prednisolone 80–100 mg/day or intravenous methylprednisolone therapy 1 g/day for 3 days repeated weekly for 3 weeks). If this is unsuccessful, either acutely or in the long term, including due to steroid complications, surgical decompression of the orbit is usually performed. Several techniques have been devised using external or transnasal endoscopic approaches. All aim to expand the orbital volume by removal of the bony walls, usually the orbital floor, medial wall, and possibly lateral wall, with incision of the orbital periosteum. There is a risk of causing or exacerbating diplopia and a lesser risk of orbital infection. Orbital radiotherapy may be an effective alternative in patients unsuitable for surgery but should be avoided in diabetics with retinopathy. Exposure keratitis due to severe proptosis may respond to lateral tarsorrhaphy.
Whether oral corticosteroids (prednisone up to 60 mg/day), with or without additional immunosuppressants, or orbital radiotherapy should be used in active disease not complicated by optic neuropathy or severe corneal exposure is controversial. Systemic steroids commonly result in improvement in symptoms, but the potential for complications limits their long-term use. Pulsed high-dose intravenous steroids appear to be more effective with fewer adverse effects than long-term oral therapy.
Eyelid retraction is often more disturbing than proptosis—both functionally, because of exposure keratitis, and cosmetically. Surgical orbital decompression may improve lid retraction, but correction of the retraction by lid surgery is safer and camouflages proptosis to some extent. The upper and lower lid retractors (aponeurosis and sympathetic muscles) can be lengthened by inserting a spacer such as eye bank sclera. Small amounts (2 mm) of lid retraction can be corrected by disinserting the retractors from the upper tarsal border. Once the ophthalmopathy is inactive, surgical orbital decompression can be performed for cosmetically unacceptable proptosis, but the risks of surgery need to be borne in mind.
Double vision may not be sufficiently bothersome to require treatment. While the ophthalmopathy is active, prisms or occlusion may be helpful. Strabismus surgery should not be undertaken until the ophthalmopathy is inactive and the ocular motility disturbance has been stable for at least 6 months. Tight muscles, usually inferior and medial recti, are recessed using adjustable sutures. Most patients can achieve at least a small area of binocular single vision in a useful position of gaze. Torsional diplopia, the result of oblique muscle involvement, complicates management. Botulinum toxin is rarely helpful in the acute or chronic stages of the disease. Some patients have intractable diplopia despite all attempts at correction.
A frequent cause of proptosis in adults and children is inflammatory pseudotumor. (The term “pseudotumor” was adopted to indicate a non-neoplastic process that produces the sentinel sign of an orbital neoplasm, ie, proptosis.) In some cases it is due to vasculitis, most commonly Wegener's granulomatosis, possibly in its limited form that may not be associated with positive serum antineutrophil cytoplasmic antibodies (ANCA). The inflammatory process can be diffuse or localized, specifically involving any orbital structure (eg, myositis, dacryoadenitis, superior orbital fissure syndrome, or optic perineuritis) or cell type (eg, lymphocytes, fibroblasts, histiocytes, and/or plasma cells). There may be extension to involve the cavernous sinuses and intracranial meninges. Onset is usually rapid, and pain is often present.
Pseudotumor is usually unilateral; when both orbits are involved, it is more often a manifestation of vasculitis. The differential diagnosis includes Graves' ophthalmopathy and orbital lymphoma.
Treatment with systemic NSAIDs, systemic corticosteroids, if necessary with other immunosuppressants (eg, cyclophosphamide) if there is underlying vasculitis, and rarely radiation, is usually effective, but there is a sclerosing variant that is very resistant to treatment. Surgery tends to exacerbate the inflammatory reaction, but biopsy may be required to confirm the diagnosis in recurrent or recalcitrant cases.
Orbital Cellulitis and Preseptal Cellulitis (Figure 13–5) and Preseptal Cellulitis
Orbital (postseptal) cellulitis, which is bacterial infection deep to the orbital septum, is the most common cause of proptosis in children. Immediate treatment is essential because delay can lead to blindness, due to optic nerve compression or infarction, or death, due to septic cavernous sinus thrombosis or intracranial sepsis. Although most cases occur in children, aged and immunocompromised individuals may also be affected.
Orbital cellulitis. Abscess draining through upper eyelid.
The orbit is surrounded by the paranasal sinuses, and part of their venous drainage is through the orbit. Most cases of childhood orbital cellulitis arise from extension of acute sinusitis through the thin ethmoid bones, and thus the organisms usually responsible are Streptococcus pneumoniae, other streptococci ,Haemophilus influenza (in countries where H influenza type b (Hib) immunization is not carried out in early infancy), and less commonly Staphylococcus aureus, including methicillin-resistant S aureus (MRSA), or Moraxella catarrhalis. In adolescents and adults, when there is often chronic sinus infection, anaerobic organisms may also be involved. If there is a history of trauma, usually penetrating orbital injury but possibly from animal bites, S aureus, including methicillin-resistant S aureus (MRSA), or Group A β-hemolytic streptococci are commonly responsible.
In comparison preseptal cellulitis, which is bacterial infection superficial to the orbital septum, is usually caused by spread of infection arising within the eyelid, such as from a horedolum (see Chapter 4), surgical or traumatic wound, or an insect or animal bite.
Orbital cellulitis is characterized by fever, pain, eyelid swelling and erythema, proptosis, chemosis, limitation of extraocular movements, and leukocytosis. Non-axial proptosis suggests sub-periosteal or intraorbital abscess. Extension to the cavernous sinus produces contralateral orbital involvement, trigeminal dysfunction, and more marked systemic illness. Intracranial extension causes meningitis and possibly brain abscess.
Few orbital diseases, except for mucormycosis (see later in the chapter), progress as rapidly as bacterial infection. Preseptal cellulitis, in which there is systemic illness with eyelid swelling and erythema but no proptosis, chemosis, or limitation of extraocular movements, is the main differential diagnosis but may also mimic the initial stages of orbital cellulitis. Other entities to be considered are rhabdomyosarcoma in children, pseudotumor, and Graves' ophthalmopathy.
A CT scan or MRI may be helpful to distinguish between preseptal and postseptal cellulitis, and is particularly important when there is concern about development of an abscess (Figure 13–6) or to identify a foreign body. MRI is better than CT to detect cavernous sinus thrombosis. Plain x-rays alone can only identify the presence of sinusitis.
Axial CT scan of left orbital abscess (arrow).
Treatment of orbital cellulitis should be initiated before the causative organism is identified. As soon as nasal, conjunctival, and blood cultures are obtained, antibiotics should be administered. Intravenous therapy is generally used, initially with a cephalosporin, such as the third-generation agents cefotaxime and ceftriaxone, or a β-lactamase-resistant drug, such as nafcillin, imipinen, or piperacillin/tazobactam. Possible anaerobic infection requires addition of metronidazole or clindamycin. Cepahalosporins are appropriate if there is a history of trauma, unless MRSA infection is likely, in which case vancomycin or clindamycin is required. For patients with penicillin hypersensitivity, vancomycin, levofloxacin, and metronidazole are recommended. Success with oral ciprofloxacin and clindamycin has been reported in uncomplicated cases.
Early consultation with an otolaryngologist is important. Nasal decongestants and vasoconstrictors help drain the paranasal sinuses. Most cases respond promptly to antibiotics. Those cases that do not respond may require surgical drainage of the paranasal sinuses. Orbital abscesses usually require surgical drainage, the route being determined by the results of CT or MRI.
Preseptal cellulitis can usually be treated with oral antibiotics, such as amoxicillin/clavulanate, but the patient should be monitored closely for development of postseptal cellulitis. Therapy should be adjusted if there is high likelihood of MRSA infection or if there is a dirty wound, in which case gram-negative organisms may need to be covered.
Diabetics and immunocompromised patients are at risk of developing severe and often fatal fungal infections of the orbit. The organisms are of the zygomycetes group, which have a tendency to invade vessels and create ischemic necrosis. Infection usually begins in the sinuses and erodes into the orbital cavity. A necrotizing reaction destroys muscle, bone, and soft tissue, not necessarily causing florid signs of orbital inflammation but severe pain, visual loss, ophthalmoplegia, and systemic upset. Examination of the nose and palate characteristically reveals black, necrotic mucosa, a smear of which shows broad branching hyphae.
Without treatment, the infection gradually erodes into the cranial cavity, resulting in meningitis, brain abscess, and death usually within days to weeks. Treatment is difficult and often inadequate. It consists of correction of the underlying disease combined with surgical debridement and administration of amphotericin B intravenously and, if possible, locally. Posaconazole is another potentially useful antifungal.
Cystic Lesions Involving the Orbit
Dermoids are not true neoplasms but benign choristomas arising from embryonic tissue not usually found in the orbit. Orbital dermoids arise from surface ectoderm and often contain epithelial structures such as keratin, hair, and even teeth. Most are cystic and filled with an oily fluid that can incite a severe inflammatory reaction if liberated into the orbit. Most dermoids occur in the superior temporal quadrant of the orbit, but they can occur at any bony suture line.
CT shows a sharp, round bony defect from the pressure of a slowly growing mass affixed to the periosteum.
Epidermoid cyst is a superficial keratin-filled mass, usually near the superior orbital rim. It may be congenital or posttraumatic. Excision is usually not difficult.
A dermolipoma is a solid mass of fatty material that occurs below the conjunctival surface, usually in the region of the lateral canthus (Figure 13–7). Hair growth on the overlying conjunctiva is not uncommon. Dermolipomas are often much larger than they appear to be, and excision may cause considerable damage to vital structures, particularly the lacrimal gland ductules leading to tear deficiency. If treatment is necessary, limited excision is usually advised.
Obstruction of drainage from a paranasal sinus may lead to its expansion to form a mucocele. Frontal or ethmoid sinus mucoceles typically present with progressive non-axial proptosis, whereas sphenoid sinus mucocele present with optic neuropathy. In either case the presentation may be rapid if there is infection. CT will usually make the diagnosis (Figure 13–8). MRI may be required to differentiate from dermoid cyst and to define the extent of the lesion. Treatment is surgical, sometimes by an endoscopic approach. Otolaryngologic and/or neurosurgical assistance is likely to be required.
CT scan of right fronto-ethmoidal mucocele (arrows). A: Axial section. B: Coronal section.
Erosion of the meninges into the orbital cavity through a congenital dehiscence in the bony sutures creates a cystic mass filled with cerebrospinal fluid known as a meningocele. If there is also brain tissue it is known as a meningoencephalocele. The resultant fluctuant mass in the superior medial orbit typically enlarges with Valsalva's maneuver. Most cases are present at birth, but those arising from the sphenoid bone may not become apparent until adolescence.
Vascular Abnormalities Involving the Orbit
Arteriovenous malformations are an uncommon cause of proptosis. Orbital venous anomalies (varices) produce intermittent proptosis, sometimes associated with pain and transient reduction of vision. Some degree of proptosis can be induced with Valsalva's maneuver or by placing the head in a dependent position. There may be acute exacerbations due to hemorrhage. MRI scan is usually diagnostic. Endovascular embolization is the preferred method of treatment. Surgery is very difficult, with risk of permanent impairment of vision.
Carotid Artery–Cavernous Sinus Fistula
The diagnosis of high flow (direct) carotid artery–cavernous sinus fistulas is usually straightforward. Although sometimes occurring spontaneously due to rupture of an intracavernous internal carotid artery aneurysm, they usually follow severe head trauma causing damage to the intracavernous internal carotid. Physical signs include marked orbital congestion with chemosis, pulsating proptosis, raised intraocular pressure, retinal hemorrhages, and ophthalmoplegia, as well as a loud bruit.
Low-flow (indirect) shunts (dural carotid cavernous sinus fistula) are usually spontaneous, most commonly being associated with diabetes and systemic hypertension, and diagnosis may be delayed by misdiagnosis such as chronic conjunctivitis. Orbital congestion, arterializations of episcleral vessels, elevated intraocular pressure, mild proptosis, and possibly a faint bruit are the typical features.
Orbital ultrasound blood flow studies with color Doppler imaging provide a noninvasive method of diagnosing carotid artery–cavernous sinus fistula, by demonstrating reversal of flow (“arterialization”) in the superior ophthalmic vein. Definitive diagnosis requires angiography, often initially by CT or MR angiography, but proceeding to catheter angiography for identification of the sites of fistulization and determining whether they are amenable to treatment. High-flow fistulas generally need to be treated by transvenous or intra-arterial balloon or coil embolization, or parent vessel occlusion. Many low-flow fistulas resolve spontaneously but intra-arterial or transvenous embolization may be required.