ABSTRACT
Thyroid-associated ophthalmopathy is the most frequent extrathyroidal involvement of Graves’ disease but it sometimes occurs in euthyroid or hypothyroid patients. Thyroid-associated ophthalmopathy is an autoimmune disorder, but its pathogenesis is not completely understood. Autoimmunity against putative antigens shared by the thyroid and the orbit plays a role in the pathogenesis of disease. There is an increased volume of extraocular muscles, orbital connective and adipose tissues. Clinical findings of thyroid-associated ophthalmopathy are soft tissue involvement, eyelid retraction, proptosis, compressive optic neuropathy, and restrictive myopathy. To assess the activity of the ophthalmopathy and response to treatment, clinical activity score, which includes manifestations reflecting inflammatory changes, can be used. Supportive approaches can control symptoms and signs in mild cases. In severe active disease, systemic steroid and/or orbital radiotherapy are the main treatments. In inactive disease with proptosis, orbital decompression can be preferred. Miscellaneous treatments such as immunosuppressive drugs, somatostatin analogs, plasmapheresis, intravenous immunoglobulins and anticytokine therapies have been used in patients who are resistant to conventional treatments. Rehabilitative surgeries are often needed after treatment.
Introduction
Thyroid-associated ophthalmopathy (TAO) is an ocular condition that frequently manifests with thyroid dysfunction, and is the most common extrathyroidal manifestation of Graves’ disease. Graves’ disease is an autoimmune disease characterized by hyperthyroidism, diffuse goiter, ophthalmopathy, and in rare cases, dermopathy. Thyroid dermopathy consists of pretibial cutaneous nodules or diffuse thickening. In addition to elevated free thyroid hormone levels and suppressed thyroid stimulating hormone (TSH) levels, the levels of serum antithyroglobulin (TG) antibodies, antithyroid peroxidase (anti-TPO), and TSH receptor antibodies levels may be elevated in Graves’ disease. Graves’ disease is the most common cause of hyperthyroidism.1 The annual incidence is 0.3% in the United States of America, 2.7% in women in the United Kingdom, and 0.3% in men in the United Kingdom. It is 6 to 7 times more common in females than males. It occurs more often in the 3rd and 4th decades.2 Although TAO is usually seen in patients with Graves’ disease (80%), it may also occur in patients with thyroid cancers or autoimmune hypothyroid due to Hashimoto’s thyroiditis (10%), as well as individuals with no thyroid disease (10%).3
Epidemiology and Pathogenesis
While TAO is 2.5- to 6-fold more common among women, severe ophthalmopathy is more common among men. Onset is generally between the ages of 30 and 50, and the disease course is more severe after age 50. Ophthalmopathy is reported to occur in 25-50% of patients with Graves’ disease and 2% of patients with Hashimoto’s thyroiditis. About 3-5% of these patients have severe ophthalmopathy.4 Most patients develop ophthalmopathy within 18 months of being diagnosed with Graves’ disease. However, ophthalmopathy onset may occur up to 10 years before and as late as 20 years after the onset of thyroid disease.5
Although the pathogenesis of TAO is not completely understood, it is known to be an autoimmune disorder. It has been established that autoimmunity develops against antigens common to the thyroid gland and the orbit. Although some support the view that the common pathogenetic antigen is TSH receptor,6 Salvi et al.7 identified a 64-kDa protein common to the thyroid gland and the orbit. Recent studies have reported upregulation of the cardiac calsequestrin gene in TAO patients and suggested that autoimmunity against calsequestrin may be a triggering factor in the pathogenesis of ophthalmopathy.8 Despite a close correlation between ophthalmopathy and TSH receptor antibodies, soon after the publication of autoimmunity against calsequestrin, autobodies against orbital fibroblast membrane antigen collagen XIII were also identified.9Reactive T lymphocytes that recognize thyroid-orbit common antigens infiltrate the orbit and extraocular muscle perimysium. This is enhanced by circulating and local adhesion molecules stimulated by cytokines. Following infiltration of the orbit with T lymphocytes, the common antigen is recognized by T-cell receptors on CD4+ T lymphocytes (Th). Cytokines secreted by Th lymphocytes activate CD8+ lymphocytes and autoantibody-producing B cells, which strengthens the immune reaction.10 These cytokines stimulate the synthesis and secretion of glycosaminoglycans (GAGs) by fibroblasts. Due to their water attracting properties, GAGs lead to periorbital edema, proptosis, and swelling of the extraocular muscles.11 Fibroblast proliferation stimulated by cytokines also plays a role in the expansion of the orbital contents. Orbital fibroblasts include preadipocytes, which turn into adipocytes with hormonal stimulation. These cells have been shown to contribute to the increase in the volume of retroorbital fat tissue.12
Recent studies have demonstrated that thyroid autoantibodies and immune system genes have an important role in predicting before the development of ophthalmopathy and determining its severity after onset. Anti-TPO antibody and anti-TG positivity rates of 90% and 50%, respectively, have been reported in the presence of ophthalmopathy.13,14
In addition to autoimmunity, genetic and environmental factors are also known to be influential in the etiopathogenesis of thyroid ophthalmopathy.
Genetic Factors
There are many studies investigating the role of genetics in the development of ophthalmopathy. In a study evaluating the ocular and palpebral findings of first and second degree relatives of patients with TAO, Graves’ disease, and Hashimoto’s thyroiditis, TAO findings such as upper eyelid retraction were present in 33% of euthyroid relatives.15 Twin studies have shown that the frequency of Graves’ disease is up to 30% in monozygotic twins, and it has been predicted that the risk of developing Graves’ disease is influenced approximately 79% by genetics and 21% by environmental factors.16
Many studies have reported polymorphisms in protein genes affecting immune function such as HLADR-3, CTLA 4, PTPN22, CD40, interleukin (IL)-2RA, FCRL3, and IL-23R, as well as genes encoding thyroid-specific proteins like TG.17
The presence of single-nucleotide polymorphisms (SNPs) in the genes of tyrosine phosphatase, which affects TSH receptor, and the genes of inflammatory cytokines IL-13, IL-21, and IL-23 has been demonstrated in TAO patients.18,19,20,21,22 Gene polymorphism for transcription regulator NF-κB1 has been associated with the development and onset age of ophthalmopathy.23 A study evaluating the relationship between major histocompatibility complex (MHC) class II human leukocyte antigen (HLA) alleles and ophthalmopathy revealed an association between the HLA-DRB1 allele and extraocular muscle involvement.24 SNPs identified in the ARID5B and NRXN3 genes may also regulate fat deposition and have a link to Graves’ disease.25,26 It has been shown that a nucleotide substitution in a TG gene promoter associated with interferon alpha (IFNα) was more common in patients with autoimmune thyroid disease. The authors stated that IFNα directly affected gene expression underlying thyroid autoimmunity via the binding of IFN regulatory factor-1 to the variant TG promoter.27 In a recent study, calsequestrin-1 gene SNP was proposed as a genetic marker for TAO.28
Environmental Factors
In individuals with the relevant genes, ophthalmopathy may be triggered by environmental factors such as stress, infectious agents, iodine, IFN and interleukin therapy, and sex steroids. Bacteria may trigger an inflammatory response either by stimulating the expression of costimulatory molecules like MHC class II or by altering presentation of their own proteins. Although there are reports in the literature linking Graves’ disease to human foamy virus and Yersinia enterocolitica infection, causal relationships could not be demonstrated.17 Cigarette use is the strongest modifiable risk factor. In fact, the risk is proportionate to the number of cigarettes smoked daily.29 TAO is more common and more severe in smokers, and smokers also relapse more often and more severely after treatment. Cawood et al.30 demonstrated that GAG production and adipogenesis increased in a dose-dependent manner in response to cigarette smoke extract in an in vitro TAO model. Moreover, smoking leads to delayed and reduced response to ophthalmopathy treatment.31
Clinical Course and Signs
Patient evaluation begins with confirming the clinical diagnosis and determining the current disease phase; finally, determining the clinical severity is necessary in order to choose appropriate treatment.
Ophthalmic findings are usually bilateral, but may also be unilateral or asymmetric. Nearly half of Graves’ disease patients have symptoms including dryness and stinging, photophobia, epiphora, diplopia, and a feeling of pressure behind the eyes.29 In a study evaluating 120 TAO patients, the most common ocular findings were eyelid retraction (91%), proptosis (62%), extraocular muscle dysfunction (42%), conjunctival hyperemia (34%), eyelid edema (32%), and chemosis (23%). Findings of optic neuropathy were rarer (6%). In the same patient series, the most common symptom was diplopia (33%), followed by pain and discomfort (30%), epiphora (21%), photophobia (16%), and blurred vision (9%).31
Subclinical involvement is present in approximately 70% of patients with Graves’ hyperthyroidism. Expansion of the extraocular muscles may be apparent on magnetic resonance imaging (MRI) and computed tomography (CT). In approximately 3-5% of patients, the disease follows a severe course with severe pain, inflammation, sight-threatening corneal ulceration, and compressive optic neuropathy.29
The clinical manifestations of TAO can be evaluated under the headings of soft tissue inflammation, eyelid retraction, proptosis, restrictive myopathy, and optic neuropathy.
Soft Tissue Inflammation
Soft tissue inflammation is often the earliest sign of TAO. Soft tissue involvement consists of periorbital edema, conjunctival hyperemia, chemosis, and superior limbic keratoconjunctivitis (SLK). Symptoms may include foreign body sensation, epiphora, palpebral and conjunctival hyperemia and edema, blurred vision, and retroorbital pain. Periorbital edema may lead to prolapse of the retroseptal adipose tissue into the eyelid, venous circulatory disturbance, and retroseptal infiltration. SLK is characterized by upper tarsal conjunctival papillae, superior bulbar conjunctival hyperemia, limbal papillary hypertrophy, punctate epitheliopathy, and filaments in the upper cornea. Thyroid function tests should be performed for all patients with SLK.
Eyelid Retraction
Upper eyelid retraction (Dalrymple’s sign) may emerge as an early sign of TAO. Upper eyelid retraction in TAO may be caused by increased sympathetic stimulation of Müller’s muscle by thyroid hormone, but may also be attributed to the formation of scar tissue between the levator muscle and surrounding tissues, or to overaction of the levator muscle contracting against a tight inferior rectus muscle (Figure 1).29 In addition to upper eyelid retraction, upper eyelid lag (von Graefe’s sign) is also an important sign. Upper eyelid lag refers to a delay in the upper eyelid following as the eye rotates downward as a patient tracks an moving object. This is also an important criterion in the early diagnosis of TAO.
Proptosis
Proptosis is spontaneous decompression resulting from enlargement of the extraocular muscles and adipose tissue, as well as orbital fat deposits and the infiltration of orbital tissues by GAGs and leukocytes (Figure 2). TAO is the most common cause of unilateral and bilateral proptosis in adults. It does not respond to hyperthyroidism treatment, and is permanent in 70% of cases. Proptosis is usually (90%) bilateral. Complications such as exposure keratopathy, corneal ulcer, and even corneal perforation may occur in cases of severe proptosis due to the eyelids not fully closing. Upper eyelid retraction may be confused with proptosis. Conditions producing pseudoproptosis include conditions in which the eyeball is enlarged, such as degenerative myopia and congenital glaucoma (buphthalmos), upper eyelid retraction, and contralateral enophthalmos.
Restrictive Myopathy
Eye movements are restricted due to edema that occurs in the extraocular muscles during the infiltrative stage and the subsequent fibrosis. Diplopia manifesting as the appearance of overlapping images is common. In primary and reading positions, it affects daily activities and causes patients significant discomfort. Despite expansion of the extraocular muscles in TAO, the muscle fibers themselves are normal. Muscle enlargement occurs due to separation of the muscle fibrils by fluid and fat deposits and by GAG material, fibrosis, scar formation, and leukocyte infiltration. Usually a single muscle is involved. While any of the six extraocular muscles may be involved, enlargement of the inferior rectus muscle is seen in most patients (Figure 3), followed by medial and superior rectus muscle involvement (Figure 4).32 Pressure exerted by a fibrotic inferior rectus muscle on the globe may cause a spike in intraocular pressure during upgaze. In some cases, extraocular muscle fibrosis may also be associated with chronically elevated intraocular pressure.33
Optic Neuropathy
Optic neuropathy develops as a result of pressure from enlarged muscles on the optic nerve or the vessels that supply it. It may present with gradual decline in visual acuity, color vision disturbance, and central or paracentral scotomas. Fundus examination is usually normal, though optic disc edema, choroidal folds, optic disc paleness may be observed. The presence of optic neuropathy is often not correlated with proptosis.34
Orbital imaging may be done with ultrasound, CD, or MRI. Ultrasound allows rapid evaluating, but requires an experienced operator. CT and MRI have the advantage of imaging the entire orbit. CT is more sensitive for showing extraocular muscle enlargement. In active disease, the extraocular muscles appear as hyperintense on T2-weighted MRI.35
Although the natural course of ophthalmopathy is not fully understood, it has an inflammatory active phase that lasts an average of 3-6 months but may be as long as 3 years, followed by a fibrotic inactive phase. About 1% of patients experience reactivation after a period of inactivity. There is no indicator signaling the beginning of the inactive phase, but stability of clinical findings for a period of 6 months may indicate transition to inactive phase.36
In 1969, Werner36 first systematically classified the clinical characteristics of TAO in order to determine severity of ophthalmopathy. He divided the ocular findings by severity into seven classes, and named the classification system with the acronym “NOSPECS” based on the first letter of each class. The classification was modified in 1977 by the American Thyroid Association.37 It is not widely used today due to several limitations, including its reliance on subjective criteria, inability to assess disease activity, and the fact that the irregular clinical progression exhibited by most patients does not conform well to the classification system.
In 1989, Mourits et al.38 developed the Clinical Activity Score (CAS) for evaluating ophthalmopathy activity (Table 1). According to this formula, which includes 10 different inflammatory changes, each finding is scored to yield an activity score between 0 and 10. In 1992, a committee formed by four thyroid societies modified the CAS and reduced the number of criteria. The modified version was published to facilitate the evaluation of ocular changes following ophthalmopathy treatment (Table 2).39
According to the European Group on Graves’ Orbitopathy (EUGOGO), a CAS score of 3 or higher defines active TAO with a 65% positive predictive value for response to radiotherapy. According to this, it can be expected that patients with higher CAS values will respond better to treatment.29,40 Regardless, the CAS has certain limitations such as being dependent on the evaluator and being inadequate for following clinical changes.41
More recently, Dolman and Rootman42 developed the VISA classification, based on 4 findings: vision, inflammation, strabismus, and appearance (Table 3). Each parameter is separately graded and scored. Active disease is defined as worsening in any of the VISA parameters. Another classification system most commonly used in evaluating the activity and severity of TAO and making treatment decisions is the EUGOGO classification (Table 4).43
Treatment
Most TAO patients have mild and nonprogressive ocular involvement which does not require treatment. Less severe ophthalmopathies tend to resolve spontaneously.3
Treatment options for TAO can be grouped into medical and surgical therapies. Medical treatment is appropriate for patients with active disease. These treatments are not effective for inactive ophthalmopathy and carry the risk of side effects. Surgical interventions can be implemented in cases where the threat to vision cannot be controlled with medical treatment, and in cases with inactive disease in order to protect function and improve appearance.
Because cigarette smoking increases the severity of ophthalmopathy and reduces treatment response, patients should be urged to quit smoking.44 Thyroid dysfunction, particularly hypothyroidism, negatively affects ophthalmopathy onset; therefore, a euthyroid state must be achieved as quickly as possible and maintained.45 Euthyroidism may be achieved with antithyroid drugs, radioactive iodine (RAI) therapy, or thyroidectomy. However, it has been shown that RAI therapy leads to new ophthalmopathy development and exacerbates existing ophthalmopathy. This effect does not occur with combined RAI and steroid therapy.46 The effect of RAI on ophthalmopathy may be explained by two mechanisms. Antigens common to the thyroid and retroorbital tissues may be released due to radiation-induced thyroid damage, and these antigens may play a role in the development of immune-mediated ophthalmopathy. Alternatively, RAI therapy may stimulate the secretion of TSH due to the rapid induction of hypothyroidism, thereby stimulating antigen production by thyrocytes.47 In contrast, a recent study reported that RAI therapy did not increase the risk of ophthalmopathy development or exacerbation.48
Topical lubricants are recommended to protect the cornea and alleviate symptoms of dryness. In addition to using artificial tear drops or gel during the day, at night the eyelids may be taped closed to prevent conjunctival exposure and ointments can be applied. Guanethidine and beta blocker eye drops can be used to treat eyelid retraction. Patients with pronounced periorbital edema may benefit from elevating the head at night. Wearing sunglasses may also provide symptomatic relief. Prismatic spectacles may be prescribed to patients with diplopia.49 Botulinum toxin injection may provide temporary improvement in upper lid retraction and restrictive myopathy.50,51
Conclusion
TAO is an autoimmune disease with significant impact on quality of life. Although in most patients ophthalmopathy is mild and nonprogressive, it is of the utmost importance that patients at risk be followed closely and treated appropriately and in a timely manner based on disease severity and activity.
