Diagnosis

The diagnosis of TED is made when 2 of the following 3 signs are present:

1. Concurrent or recently treated immune-related thyroid dysfunction:

   1. Graves hyperthyroidism

   2. Hashimoto thyroiditis

   3. Presence of circulating thyroid antibodies without a coexisting dysthyroid state (partial consideration given): thyroid-stimulating hormone–receptor (TSH-R) antibodies, thyroid-binding inhibitory immunoglobulins, thyroid-stimulating immunoglobulins, antimicrosomal antibodies

2. Typical ocular signs:

   1. Chemosis and/or caruncular edema (see Fig 4-7)

   2. Restrictive strabismus in a typical pattern (see Fig 4-8)

   3. Unilateral or bilateral eyelid retraction with typical lateral flare (see Fig 4-9)

   4. Unilateral or bilateral proptosis (in comparison with old photos of the patient)

   5. Compressive optic neuropathy

   6. Fluctuating eyelid edema and/or erythema

3. Radiographic evidence of TED: unilateral or bilateral fusiform enlargement any of the rectus muscles and/or the levator muscle complex (Figs 4-11, 4-12).

Serologic testing, using serum thyroid-stimulating hormone (TSH), triiodothyronine (T3), and free thyroxine (T4) levels, is well established in the diagnosis of thyroid disease. However, the usefulness of these tests in monitoring TED treatment and progression is unclear, because the systemic disease and the eye disease are discordant.

Tests of autoimmune function may be helpful in evaluating disease activity and severity. TSH-R antibody testing can be performed by measuring all immunoglobulins targeting the TSH-R (eg, the thyrotropin-binding inhibitory immunoglobulin [TBII] test) or by measuring only the stimulating antibodies (eg, the thyroid-stimulating immunoglobulin [TSI] assay).

These tests may help identify the cause of the thyroid disease and may help identify patients at high risk for TED; however, results should be interpreted with caution because the diagnosis of TED is based mainly on clinical findings. Thyroid peroxidase antibody testing has replaced antimicrosomal antibody testing; however, the presence of this antibody does not correlate with TED activity or severity or TSI levels. Similarly, thyroglobulin antibody levels do not correlate with TED. Insulin-like growth factor I (IGF-I) antibody levels may represent a future area of serologic testing for TED; however, no current recommendations exist.

Patients presenting with only orbital signs require observation for other orbital diseases or the development of a dysthyroid state.

• Mourits MP, Prummel MF, Wiersinga WM, Koornneef L. Clinical activity score as a guide in the management of patients with Graves’ ophthalmopathy. Clin Endocrinol (Oxf). 1997;47(1):9–14.

• Srinivasan A, Kleinberg TT, Murchison AP, Bilyk JR. Laboratory investigations for diagnosis of autoimmune and inflammatory periocular disease: Part II. Ophthalmic Plast Reconstr Surg. 2017;33(1):1–8.

Pathogenesis

Orbital fibroblasts, through the expression of characteristic surface receptors, gangliosides, and proinflammatory genes, play an active role in modulating the inflammatory process. Unlike fibroblasts from other body sites, orbital fibroblasts express CD40 receptors, which are generally found on B cells. When engaged by T-cell–bound CD154, several fibroblast proinflammatory cytokines are upregulated, including interleukin-6 (IL-6) and interleukin-8 (IL-8), as well as prostaglandin E2, increasing synthesis of hyaluronan and glycosaminoglycan (GAG). This upregulation of orbital fibroblast GAG synthesis represents an essential aspect of the pathology of TED, and it occurs at a rate 100 times that of abdominal fibroblasts from the same patient. Therapeutic levels of corticosteroids dampen the upregulation cascade.

Orbital fibroblasts, which are embryologically derived from the neural crest lineage, possess developmental plasticity. A subpopulation of orbital fibroblasts appears capable of undergoing adipocyte differentiation, contributing to the expansion of orbital fat that predominates in some patients.

A circulating immunoglobulin that recognizes and activates the insulin-like growth factor I receptor (IGF-IR) expressed on the surface of orbital fibroblasts of individuals with Graves disease may stimulate orbital fibroblasts to secrete GAGs, cytokines, and chemoattractants. These latter signaling families may contribute to orbital inflammation and congestion.

• Kazim M, Goldberg RA, Smith TJ. Insights into the pathogenesis of thyroid-associated orbitopathy: evolving rationale for therapy. Arch Ophthalmol. 2002;120(3):380–386.

• Naik V, Khadavi N, Naik MN, et al. Biologic therapeutics in thyroid-associated ophthalmopathy: translating disease mechanism into therapy. Thyroid. 2008;18(9):967–971.

• Tsui S, Naik V, Hoa N, et al. Evidence for an association between thyroid-stimulating hormone and insulin-like growth factor 1 receptors: a tale of two antigens implicated in Graves’ disease. J Immunol. 2008;181(6):4397–4405.

Epidemiology

A 1996 epidemiologic study of white patients with TED in the United States determined that the overall age-adjusted incidence per 100,000 population per year was 16 cases for women compared with 3 cases for men. The peak incidences occurred in the age groups 40–44 years and 60–64 years in women and 45–49 years and 65–69 years in men. Development of TED is up to 7 times as likely for smokers when compared to nonsmokers.

Clinical features

Among patients with TED, about 90% have Graves hyperthyroidism, 6% are euthyroid, 3% have Hashimoto thyroiditis, and 1% have primary hypothyroidism. A close temporal relationship exists between the development of hyperthyroidism and the development of TED: in about 20% of patients, the diagnoses are made at the same time, and in about 60% of patients, the eye disease occurs within 1 year of onset of the thyroid disease. For patients who have no history of abnormal thyroid function or regulation at the time TED is diagnosed, the risk for development of thyroid disease is about 25% within 1 year and 50% within 5 years. Although hyperthyroidism is present or will develop in most patients with TED, only about 30% of patients with autoimmune hyperthyroidism will develop TED.

Pretibial myxedema accompanies TED in about 4% of patients. Acropachy (soft-tissue swelling and periosteal changes affecting the distal extremities, principally fingers and toes) accompanies TED in about 1% of patients. Both are associated with a poor prognosis for the orbitopathy. Myasthenia gravis occurs in fewer than 1% of patients and should be considered when ptosis accompanies TED.

The most frequent presenting ocular symptoms and signs of TED are a dull, deep orbital pain or discomfort (30% of patients), lid lag with downgaze (unilateral or bilateral, 50%; see Fig 4-10), and upper eyelid retraction (unilateral or bilateral, 75%). Symptomatic dysthyroid optic neuropathy is present in less than 2% of eyes at the time of diagnosis of TED.

Upper eyelid retraction occurs in more than 90% of patients during their clinical course (see Fig 4-9); exophthalmos (unilateral or bilateral) in 60%; restrictive extraocular myopathy in 40%; and optic neuropathy (unilateral or bilateral) in 5%. Only 5% of patients develop the complete constellation of these 4 classic findings and hyperthyroidism. Some degree of diplopia is reported by about 17% of patients, lacrimation or photophobia by 15%–20% of patients, and blurred vision by 7% of patients.

• Bartley GB, Fatourechi V, Kadrmas EF, et al. Clinical features of Graves’ ophthalmopathy in an incidence cohort. Am J Ophthalmol. 1996;121(3):284–290.

Treatment and prognosis

TED is a self-limiting disease that on average lasts 1 year in nonsmokers and between 2 and 3 years in smokers. After the active disease plateaus, a quiescent “burnt-out” phase that follows Rundle’s curve ensues (Fig 4-13). Reactivation of inflammation occurs in 5%–10% of patients over their lifetime.

Although several clinical scoring systems to guide TED evaluation and treatment exist, including NO SPECS, Clinical Activity Score (CAS), and VISA, no system prevails. The CAS and VISA systems each assign points for various findings; the CAS adds extra parameters for follow-up visits and the VISA uses the same scale for both initial and follow-up visits. Treatment of patients with TED follows a stepwise and graded approach based on symptoms, clinical examination, and ancillary testing (Tables 4-3, 4-4).

Table 4-3 VISA and CAS Inflammatory Scoring Systems

Most patients with TED in the active phase require only smoking cessation and supportive care, including use of topical ocular lubricants. The following may also be helpful:

• topical cyclosporine, which may reduce ocular surface irritation

• a reduced-salt diet and sleeping with the head of the bed elevated, which may limit orbital edema

• wearing wraparound sunglasses, which may relieve exposure and dry eye symptoms

• temporary prism glasses, which may help maintain binocular fusion

In addition, selenium supplementation may improve the course of disease, especially in patients heralding from selenium-deficient regions. Neurotoxins can temporarily improve upper eyelid retraction by weakening the eyelid elevators. Neurotoxins can also be used to treat restrictive strabismus by weakening affected extraocular muscle(s).

Severe orbital inflammation may mandate early intervention to improve corneal exposure, globe subluxation, or optic neuropathy. Therapies generally attempt to decrease orbital congestion and inflammation (eg, glucocorticoids, biologics, radiotherapy), mechanically protect the cornea (eg, tarsorrhaphy), expand the orbital bony volume (eg, bony orbital decompression), or reduce orbital soft tissue volume (eg, fatty orbital decompression).

Table 4-4 Management of Thyroid Eye Disease

Mild disease Observation Patient education and lifestyle changes Smoking cessation Salt restriction Elevation of head of bed Use of sunglasses Ocular surface lubrication Establishment of a euthyroid state Oral selenium Moderate disease Topical cyclosporine Eyelid taping at night Moisture goggles or chambers Prism glasses or selective ocular patching Moderate-dose oral corticosteroid therapy Severe disease High-dose intravenous corticosteroid therapy Surgical orbital decompression (followed by strabismus surgery and/or eyelid surgery) Periocular radiotherapy Refractory disease Steroid-sparing immunomodulators

Establishing the euthyroid state represents a mainstay of therapy. Hyperthyroidism is most commonly treated with antithyroid drugs and sometimes with radioactive iodine (RAI). In some patients, RAI treatment may worsen TED, presumably because the TSH-R antigen release incites an enhanced immune response. In addition, hypothyroidism occurring after RAI treatment may exacerbate TED via stimulation of TSH-R. Exacerbation of TED after RAI treatment may occur more commonly in hyperthyroid patients with severe, active TED, those with elevated T3 levels, and smokers. Oral glucocorticoid treatment tapered over 3 months may limit TED progression in patients with risk factors such as these, but it is not indicated for patients without preexisting TED and without risk factors. Another strategy, termed block-and-replace therapy (eg, with iodine 131, methimazole, and thyroxine) reduces exacerbation of eye findings by limiting posttreatment TSH spikes. A third strategy, usually reserved for patients whose disease is refractory to RAI or those with severe TED, involves thyroidectomy, which creates hypothyroidism without extended antigen release.

Patients with active TED featuring compressive optic neuropathy or other significant activity based on scoring systems (eg, VISA, CAS) may benefit from IV glucocorticoid treatment. Typical regimens vary from 500 mg to 1 g methylprednisolone weekly for 6–12 weeks, with a maximum dose of approximately 6 g in most cases and up to 8 g in severe cases. Hepatic function should be checked before administration and monitored throughout treatment due to potentially fatal hepatotoxicity. For oral glucocorticoids, which are now less commonly used than they were in the past, the usual starting dose is 1 mg/kg prednisone for 2–4 weeks until a clinical response is apparent. The dose is then reduced as rapidly as possible, based on the clinical response of optic nerve function. Although effective, high-dose glucocorticoids are associated with an extensive list of potential systemic adverse effects, limiting their long-term use. Refractory cases of optic neuropathy and vision-threatening exposure keratopathy may require additional treatments, such as orbital radiotherapy or decompressive surgery.

Some reports suggest that treatment with fractionated orbital radiotherapy improves compressive optic neuropathy and other signs of TED in some patients, possibly by inducing terminal differentiation of fibroblasts and killing tissue-bound monocytes, which play an important role in antigen presentation. Recent evidence has suggested it may provide a protective effect against the development of optic neuropathy. Given the biologic effects of radiation, it is likely more useful in the active phase of the disease. Although radiation has been used for decades, a wealth of data exists to both support and refute its use, with and without the use of glucocorticoids, for many signs and symptoms of TED. Radiation therapy carries a rare risk of exacerbating diabetic retinopathy or other ischemic retinopathies.

Treatment with rituximab may affect the clinical course of TED by blocking the CD20 receptor on B lymphocytes; however, it does not appear to target the central mechanisms of the disease, and most clinicians currently use this only as a second-line therapy in select cases. Tocilizumab, a monoclonal IL-6 antibody, may reduce inflammatory signs and even TSI via an upstream effect on the inflammatory cycle. A variety of other anti-inflammatory, antimetabolite, and biologic agents have been employed with limited success.

In a recent clinical trial, teprotumumab, a human monoclonal antibody inhibitor of IGF-IR, reduced exophthalmos and the CAS in patients with active ophthalmopathy. Teprotumumab may specifically target the autoimmune process underlying TED. This new therapeutic agent appears well tolerated; hyperglycemia in patients with diabetes mellitus represents the main adverse effect.

In patients with active TED, orbital decompression treats optic neuropathy and severe exposure keratopathy that is refractory to medical therapy. In the postinflammatory phase of the condition, the first stage of surgical rehabilitation is decompression to address disfiguring or symptomatic proptosis. Preoperative CT imaging details the relative contributions of extraocular muscle enlargement and fat expansion to the proptosis (see Figs 4-11, 4-12). Patients with more enlargement of the orbital fat compartment (type I orbitopathy) may benefit from more fatty decompression, whereas patients with more extraocular muscle enlargement (type II orbitopathy) may benefit from more bony decompression. Fat and bone removal can be combined, graded, and tailored to achieve different amounts of proptosis reduction while minimizing adverse effects, such as diplopia, hypoglobus, and sinusitis. See Chapter 7 for further discussion of orbital decompression.

Because decompression may produce or worsen diplopia, it should precede strabismus surgery, which may help restore single vision in patients with intractable diplopia in primary gaze or in the reading position. Prisms represent another option for patients with relatively comitant strabismus or for patients with a small deviation after strabismus surgery.

Surgery to recess the rectus muscles can change eyelid position, so strabismus surgery typically precedes eyelid repositioning surgery. Levator and/or Müller muscle recession improves upper eyelid retraction to decrease corneal exposure and help improve appearance. The lower eyelids can be repositioned as well, typically by recessing the eyelid retractors, with or without a spacer graft or during a midface-lift. Finally, the last stage of surgery includes redraping of the eyelid skin and subcutaneous tissues. These techniques often address redundant skin and fatty tissues in addition to concomitant and independent periocular aging changes.

Elective orbital decompression, strabismus surgery, and eyelid retraction repair are usually not considered until achieving a euthyroid state with stable ophthalmic signs for at least 6 to 9 months.

Fortunately, treatment usually mitigates vision loss from optic neuropathy and prism glasses typically treat persistent diplopia. Subjectively, however, more than 50% of patients believe that their eyes look abnormal, and 38% of patients are dissatisfied with the appearance of their eyes. Thus, although significant long-term functional impairment from TED remains uncommon, the disease leaves lasting psychological and aesthetic sequelae.

• Bartalena L, Marcocci C, Bogazzi F, et al. Relation between therapy for hyperthyroidism and the course of Graves’ ophthalmopathy. N Engl J Med. 1998;338(2):73–78.

• Chundury RV, Weber AC, Perry JD. Orbital radiation therapy in thyroid eye disease. Ophthalmic Plast Reconstr Surg. 2016;32(2):83–89.

• Dolman PJ, Rootman J. VISA classification for Graves orbitopathy. Ophthalmic Plast Reconstr Surg. 2006;22(5):319–324.

• Smith TJ, Kahaly GJ, Ezra DG, et al. Teprotumumab for thyroid-associated ophthalmopathy. N Engl J Med. 2017;376(18):1748–1761.

Excerpted from BCSC 2020-2021 series: Section 10 - Glaucoma. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.