Thyroid-Associated Orbitopathy
Introduction
Thyroid-associated orbitopathy, also known as Graves’ ophthalmopathy/orbitopathy (hereinafter referred to as GO), is a manifestation of an autoimmune process directed against the tissues surrounding the eyeball (1). The most commonly used term for this condition—ophthalmopathy—is not entirely accurate because the organ of vision itself (Greek ophthalmos – eye) is not directly affected (2).
GO is the most common cause of ocular proptosis (exophthalmos) in adults and occurs in up to 50% of patients with Graves’ disease. Therefore, a patient presenting to a family physician with protrusion of the eyes, particularly when bilateral, should first be evaluated for thyroid disease (3). Among thyroid disorders, Graves’ disease most commonly causes ocular involvement (hence the term Graves’ ophthalmopathy/orbitopathy). However, ophthalmopathy may also occur in patients with no current or previous history of hyperthyroidism (ocular or euthyroid Graves’ disease) and in patients with chronic autoimmune thyroiditis and hypothyroidism (1).
The management of patients with GO is complex and is not limited to treatment of the orbitopathy itself. It is also important to control thyroid function and maintain euthyroidism, avoid factors that may exacerbate GO, such as smoking, and, if radioactive iodine is administered, provide prophylactic oral glucocorticoids. Measures to relieve symptoms should also be recommended, including ocular lubrication with artificial tears or ointments, prism glasses to correct strabismus, sleeping with the head elevated, and botulinum toxin injections into the upper eyelid (1).
Pathogenesis of GO
The pathogenesis of GO is not fully understood (2). Ocular involvement is thought to occur because extraocular muscle cells and retrobulbar fibroblasts express class II human leukocyte antigens on their surface—the same antigens expressed by thyrocytes in patients with autoimmune thyroid disease. Because of these cell-surface antigens, these cells may function as antigen-presenting cells and initiate an autoimmune process by activating T lymphocytes and local dendritic cells (2). The principal antigen involved in initiating the subsequent autoimmune process is the thyroid-stimulating hormone (TSH) receptor (2, 4).
Activated T lymphocytes infiltrate the extraocular muscles and retrobulbar connective tissue and release cytokines, including tumor necrosis factor alpha and interferon gamma, which stimulate fibroblasts to produce increased amounts of glycosaminoglycans. Glycosaminoglycans are hydrophilic and therefore promote fluid accumulation within the tissues, increasing the volume of the extraocular muscles and the retrobulbar connective and adipose tissues.
As orbital pressure increases, the eyeball is displaced forward, and compression of the optic nerve may occur. Extraocular muscle function and venous drainage from the orbital structures may also become impaired. As the eye protrudes, the eyelids may no longer completely cover the eyeball, potentially resulting in corneal damage (2). The inflammation itself may persist for up to 1–2 years, after which connective tissue develops in the previously inflamed areas (2).
Table 1. Symptoms That May Be Reported by a Patient With GO (2, 4)
| GO Symptoms |
|---|
| Dry eyes |
| Foreign body sensation in the eyes |
| Eyelid swelling |
| Eye tearing, especially in cold air, wind, or bright light |
| Feeling of pressure or pain in the eyes |
| Double vision |
| Decreased visual acuity |
| Visual field loss |
| Impaired color vision |
| Difficulty looking upward |
| Eyes “bulging” out of the orbits |
| Other symptoms |
Diagnosis of GO
GO is the most common cause of proptosis (exophthalmos) in adults (3). Clinically, the disease is usually relatively easy to suspect, particularly when it develops together with thyrotoxicosis or in a patient with a history of thyrotoxicosis, bilateral exophthalmos, and acute or subacute swelling of the structures surrounding the eyeball (2, 4).
In 40% of patients, ocular symptoms occur simultaneously with the clinical manifestations of thyrotoxicosis; in 20%, ocular symptoms develop before thyrotoxicosis; in another 20%, ocular symptoms develop within 6 months after the onset of thyrotoxicosis; in approximately 10%, ocular symptoms occur after treatment of thyrotoxicosis, most commonly following radioactive iodine therapy; and in up to 10%, GO may occur without thyroid dysfunction (2).
Therefore, when evaluating a patient with exophthalmos, laboratory tests assessing thyroid function should be performed first: TSH, FT4 (free thyroxine), and FT3 (free triiodothyronine). Antibody testing is also useful, including anti-TSHR (antibodies against the TSH receptor) and anti-TPO (antibodies against thyroid peroxidase) (4).
Depending on the stage and severity of inflammation, patients may report various ocular symptoms (Table 1) (2, 3). On physical examination, the conjunctiva should be inspected for swelling (chemosis) and injection (visible small conjunctival blood vessels), and swelling of the periorbital tissues should be assessed. The presence of eyelid retraction should also be evaluated by determining whether there is a gap between the upper and lower eyelid margins; if such a gap is present, the risk of corneal damage is increased.
Eye movements should be examined. Convergence is most commonly impaired, upward gaze may be restricted, and diplopia frequently occurs because of extraocular muscle dysfunction.
The degree of proptosis can be measured using an exophthalmometer. The distance is measured from the lateral bony orbital rim to an imaginary perpendicular line drawn through the most protruding point of the cornea. Visual acuity, color vision, and visual fields should also be assessed (2).
If optic nerve involvement is suspected—such as unexplained sudden deterioration of vision, impaired color vision, or a previous sudden “prolapse” of the eyeball from the orbit—or if corneal damage is suspected because of a gap between the eyelids, severe tearing, intense photophobia, and eyelid spasm, the patient must be referred immediately to a specialized ophthalmology center (1).
In cases of unilateral ophthalmopathy without thyroid dysfunction, imaging studies should be performed first to exclude an orbital mass lesion (2). Orbital magnetic resonance imaging (MRI) provides the best visualization of orbital contents. It allows assessment of extraocular muscle swelling, increased retrobulbar adipose and connective tissue, and visualization of the optic nerve. With fat-suppression sequences, the activity of inflammation within the orbital tissues can also be evaluated (2, 3). When MRI is unavailable, computed tomography, which provides the best visualization of the bony orbital structures, or orbital ultrasonography may be performed (3).
General Recommendations for the Care of Patients With GO
In addition to specific treatment for GO, all patients, regardless of disease severity, should receive treatment for any underlying thyroid dysfunction. Patients should be advised to avoid factors that may worsen the course of GO, and symptomatic measures should be prescribed when necessary (1).
The course of GO is more severe when thyroid function is not adequately controlled. Therefore, euthyroidism should be achieved and maintained as quickly as possible, with treatment of both hypothyroidism and hyperthyroidism (1). Several approaches can be used to manage hyperthyroidism: administration of antithyroid drugs beginning with a high dose and gradually reducing it until euthyroidism is achieved; administration of a high dose of antithyroid medication sufficient to induce hypothyroidism, with additional levothyroxine replacement; partial or total thyroidectomy; or radioactive iodine therapy.
However, clinical trial data are insufficient to demonstrate that any one of these approaches is superior to the others (1). Currently, all of these methods are considered appropriate. Even radioactive iodine therapy, which may worsen the course of GO, can be used when accompanied by prophylactic oral glucocorticoids (1).
GO is known to have a more severe course in smokers, and the effectiveness of specific GO treatment is lower in smokers than in nonsmokers (1). The effect of smoking on GO severity also correlates directly with the number of cigarettes smoked per day. Therefore, all patients with GO should be informed about the effects of smoking on ophthalmopathy and encouraged to stop smoking (1).
Measures for relieving GO symptoms include ocular lubrication with artificial tears or ointments, with ointments being more suitable for nighttime use; prism glasses to correct strabismus; botulinum toxin injections into the upper eyelid, particularly in patients with upper eyelid retraction and performed only by an experienced specialist; sleeping with the head elevated; and wearing dark glasses (1).
Table 3. Criteria for Calculating the GO Activity Index*
| Criteria |
|---|
| Spontaneous retrobulbar pain |
| Pain on attempted upward or downward gaze |
| Eyelid redness |
| Conjunctival redness |
| Eyelid swelling |
| Conjunctival swelling |
| Inflammation of the lacrimal caruncle (Lat. caruncula lacrimalis) or the semilunar fold of the conjunctiva (Lat. plica semilunaris) |
* If ≥3 signs are present, the disease is considered active (1).
Specific Treatment of GO
The treatment strategy for GO is determined by three main criteria: disease severity, degree of disease activity, and the patient’s quality of life with GO (1). Extensive information on how these criteria should be assessed is provided by the European Group on Graves’ Orbitopathy (EUGOGO). Detailed recommendations on how to perform an eye examination and assess various possible clinical signs and symptoms are also available.
To determine disease severity, the following signs are assessed:
- gap between the upper and lower eyelid margins;
- eyelid swelling;
- eyelid redness;
- conjunctival redness;
- conjunctival swelling;
- inflammation of the lacrimal caruncle (Lat. caruncula lacrimalis) or the semilunar fold of the conjunctiva (Lat. plica semilunaris);
- exophthalmos;
- strabismus subjectively experienced by the patient and its degree;
- extraocular muscle involvement;
- corneal involvement;
- optic nerve involvement (1).
Table 2 shows how each sign should be assessed when determining disease severity (1).
The choice of treatment is based on the severity of the disease.
Table 2. GO Severity According to the Expression of Clinical Signs
| Sign | Mild GO | Moderate-to-Severe GO | Very Severe GO* |
|---|---|---|---|
| Eyelid aperture | <2 mm | ≥2 mm | |
| Periorbital tissue involvement | Mild | Moderate and pronounced | |
| Exophthalmos | <3 mm above the normal value for race and sex | ≥3 mm above the normal value for race and sex | Optic nerve involvement and/or corneal involvement |
| Diplopia | Absent or intermittent | Intermittent or constant | |
| Corneal involvement | Correctable with lubricating agents |
* Very severe GO is separately referred to as a sight-threatening form (1).
In very severe GO (this form of the disease is described as sight-threatening), urgent treatment is indicated (1). If optic nerve involvement is identified, treatment with high-dose intravenous glucocorticoid pulses is recommended. If treatment is ineffective or the response is unsatisfactory within 1–2 weeks, if a more rapid effect is required, or if glucocorticoid adverse reactions are to be avoided, orbital decompression surgery is recommended. Both high-dose intravenous glucocorticoid pulse therapy and decompression surgery should be performed in specialized centers experienced in these treatments (1).
In cases of corneal involvement, treatment must be started immediately: continuous lubrication of the corneal surface; if necessary, temporary blepharorrhaphy (suturing of the eyelids) or tarsorrhaphy (suturing of the eyebrows and eyelids) may be performed until the corneal lesion heals; if these measures are ineffective, treatment with systemic glucocorticoids or orbital decompression surgery may be considered. If corneal perforation occurs or the lesion is very deep, antibiotic treatment is administered; amniotic membrane implantation or corneal transplantation may be required (1). Once the corneal lesion has healed, preventive measures are important to avoid recurrence (1).
In moderate-to-severe GO, disease activity determines the choice of treatment method (1). Table 3 presents the criteria used to calculate the disease activity index (1). Calculation of the disease activity index is based on the principle that immunosuppressive treatment will be effective only when the disease is active, with acute inflammation classically characterized by redness, swelling, and pain, and will be ineffective once the inflammation has subsided (5). Immunosuppressive treatment, if the disease is active, or surgery, if the disease is inactive, is recommended after considering whether the risks associated with treatment are justified by the negative impact of GO on the patient’s daily life (1).
Thus, the first-line treatment for active moderate-to-severe GO is intravenous glucocorticoid pulse therapy. There are no data indicating which treatment regimen is optimal. To reduce adverse reactions associated with this treatment, it is recommended that the cumulative methylprednisolone dose should not exceed 8 g during a single treatment course (1).
Another appropriate treatment for active moderate-to-severe GO is external orbital radiotherapy. It destroys T lymphocytes accumulated in the retrobulbar tissue (5). This method is particularly suitable for patients with diplopia or restricted eye movements. It is recommended that the cumulative radiation dose to one orbit should not exceed 20 Gy during a treatment course. It should be noted that radiotherapy may cause a temporary worsening of ocular symptoms, which may be alleviated with glucocorticoids (1). Increasing clinical trial evidence indicates that the best treatment effect in active moderate-to-severe GO is achieved by combining oral glucocorticoids with radiotherapy (1).
If GO is moderate-to-severe and inactive, surgical treatment is recommended. It may be performed when the disease has been inactive for at least 6 months. The sequence of surgical procedures should be carefully planned, and the recommended order is orbital decompression to correct exophthalmos, correction of strabismus, and eyelid surgery, which may also include the eyebrows (1).
In mild GO, specific treatment is not indicated because the risks associated with treatment are considered to outweigh the potential benefits (1). If quality of life is severely impaired by the disease, specific treatment may be considered. A disease-specific quality-of-life questionnaire is particularly useful in this situation (1). There is evidence that selenium administered in mild GO (100 μg twice daily for 6 months) may reduce damage to the soft tissues surrounding the eye and improve quality of life (6).
The course of GO varies between individuals, and this should not be forgotten when assessing treatment effectiveness. Over time, GO changes slightly in some patients, continuously improves or worsens in others, and sometimes follows a fluctuating course characterized by alternating periods of improvement and exacerbation (5).
Other Treatment Options for GO
Rituximab may substantially improve the course of the disease in some patients with moderate-to-severe GO. It is a biological therapy—a monoclonal antibody directed against the CD20 antigen on B lymphocytes. Rituximab causes B-lymphocyte depletion and, in GO, reduces the amount of antibodies against the TSH receptor and the number of B lymphocytes accumulated in retrobulbar tissues (5). However, one of the most important adverse reactions associated with rituximab treatment is immunosuppression, which limits its use. Reliable clinical trial data demonstrating the effectiveness of this treatment are currently lacking. Rituximab treatment is considered potentially suitable only for patients selected according to specific criteria who have moderate-to-severe, recently developed GO (5).
Somatostatin analogues have been investigated as a possible alternative treatment for GO, based on the finding that fibroblasts in retrobulbar tissues have somatostatin receptors and that GO activity correlates with the intensity of uptake observed on octreotide scintigraphy. Clinical trials have not demonstrated that the clinical efficacy of somatostatin analogues differs substantially from placebo; therefore, they are not used to treat GO (5).
Table 3. Criteria for Calculating the GO Activity Index*
| Criteria |
|---|
| Spontaneous retrobulbar pain |
| Pain on attempted upward or downward gaze |
| Eyelid redness |
| Conjunctival redness |
| Eyelid swelling |
| Conjunctival swelling |
| Inflammation of the lacrimal caruncle (Lat. caruncula lacrimalis) or the semilunar fold of the conjunctiva (Lat. plica semilunaris) |
* If ≥3 signs are present, the disease is considered active (1).
Summary
GO is a manifestation of an autoimmune process directed against the tissues surrounding the eyeball. The disease is usually readily suspected clinically, particularly when it develops together with thyrotoxicosis or in a patient with a history of thyrotoxicosis, bilateral exophthalmos, and acute or subacute swelling of the structures surrounding the eyeball.
Specific treatment for GO is selected according to disease severity and activity. Very severe GO is treated with intravenous glucocorticoid pulse therapy and decompression surgery. If corneal involvement is present, continuous lubrication of the corneal surface and appropriate antibiotic therapy are administered, and surgical interventions may be required. The first-line treatment for active moderate-to-severe GO is intravenous glucocorticoids, whereas decompression or corrective surgery may be performed in moderate-to-severe inactive disease. Specific treatment is not recommended for mild disease.
General measures may help relieve ocular symptoms and are also recommended in more severe forms of the disease: achieving and maintaining euthyroidism as quickly as possible, informing patients about the effects of smoking on orbitopathy and encouraging smoking cessation, and recommending symptomatic measures such as artificial tears or ointments to lubricate the eyes, prism glasses to correct strabismus, botulinum toxin injections into the upper eyelid, sleeping with the head elevated, and wearing dark glasses.
Prepared by Vilija Guntaitė, MD
