Introduction
Thyroid-associated orbitopathy (TAO), thyroid eye disease (TED), dysthyroid/TAO, and Graves orbitopathy all refer to a poorly understood autoimmune phenomenon resulting in the adipogenesis of orbital fat. An estimated 40% of patients with Graves disease develop TAO. Up to 20% of patients presenting with thyroid orbitopathy are concurrently diagnosed with Graves disease. Affected populations naturally parallel that of Graves disease, and TAO occurs most commonly in middle aged females. The severity of the disease varies, ranging from mild dry-eye discomfort to severe vision-threatening optic neuropathy. Late age of onset, longer duration of Graves hyperthyroidism, and smoking are associated with an increased risk of TED. Cosmetically disfiguring changes such as exophthalmos and eyelid retraction occur. Interestingly, clinically evident thyroid orbitopathy (proptosis and eyelid retraction) may precede the onset of clinical hyperthyroidism. A smaller percentage of patients diagnosed with TAO are euthyroid and develop Graves disease several months or years later. Whereas TAO is often obvious on physical examination, imaging may prompt the initial diagnosis of Graves disease and is useful for planning surgical decompression. Characteristic radiographic manifestations include proptosis secondary to extraocular muscle (EOM) enlargement and gross expansion of orbital fat. EOM enlargement in patients without clinically evident eye involvement has been reported in up to 70% of patients. Thus radiographically detectable disease heralds underlying Graves.
Evolution: Overview
Figs. 39.1 and 39.2 illustrate the anatomy and evolution of thyroid-associated orbitotomy. Table 39.1 presents an overview of its characteristics.
| Demographics | Female: 40–50 years old Risk factors: Smoking |
| Underlying disease process | Autoimmune thyroid disease |
| Key imaging characteristics | Enlargement of extraocular muscle bellies with sparing of the tendon insertions Low EOM attenuation at later stages Normalization of muscle bulk at late fibrotic stage |
| Variations | Proliferation of orbital adipose without EOM enlargement |
| Complications | Restrictive myopathy Mass effect/exophthalmos Corneal ulceration Optic nerve compression/blindness |
| Treatment | Corticosteroids, external beam radiation Vision-threatening disease: surgical decompression |
| Differential diagnosis | Orbital pseudotumor Infection (most common orbital disease process) Lymphoma Metastasis Sarcoid |
Evolution: In Greater Depth
Rundle first plotted the natural history of TAO, quantified as “ocular prominence” measured in millimeters versus time. This graph is often referred to as Rundle’s curve by clinicians well acquainted with TAO. Variations of this basic graph are often clinically referenced as a tool to roughly predict the disease’s course. It depicts disease severity based on course of disease from two patients who were followed with exophthalmometry measurements over a 30-month period. An adaptation is illustrated in Fig. 39.3 . At 10 to 15 months, Rundle recorded peak proptosis in both eyes of each of these patients, marking the transition from the “active” to “inactive” phase of disease. Subsequent recession toward a near premorbid state was documented at 30 months as the extent of proptosis gradually reduced during the “inactive” phase of disease.
Graves orbitopathy has a somewhat characteristic pattern of EOM involvement. There may be unilateral or bilateral, often asymmetric, enlargement of the muscle belly with sparing of the tendinous insertions to the globe. The most common EOMs involved in order of decreasing frequency are as follows: inferior, medial, superior, and lateral rectus. The inferior and superior oblique muscles may be involved. This is remembered by the mnemonic IM SLO. However, the most commonly involved orbital muscle is the levator palpebrae superioris, whose enlargement is related to characteristic upper eyelid retraction. During the initial stages of disease, EOMs show a spindle-like thickening, retaining a fusiform appearance and demarcated borders. EOM expansion and dysfunction occurs, leading to restrictive myopathy. Over time, EOM attenuation decreases ( Figs. 39.2 and 39.4 ). Early histologic investigations showed the replacement of normal interstitial muscular substance with low-attenuation material, reflecting a combination of inflammatory white cells, orbital fibroblasts, and hydrophilic mucopolysaccharides. Hyaluronate is often cited as major contributor to the low attenuation of EOM in TAO. However, in vitro imaging of synthetic hyaluronate shows nonfatty imaging characteristics. Late stages may progress to the fibrotic stage. Radiographically, this is demonstrated by the loss of gross muscular volume (see Figs. 39.2 and 39.4 ).
Magnetic resonance imaging (MRI), ultrasound, color Doppler ultrasound, and nuclear octreotide scans are imaging methods that supplement clinical assessment tools for determining disease stage. Edematous orbital muscles appear hyperintense on T2-weighted MRI sequences, indicating active disease. In later disease, the T2 hyperintense signal disappears as fibrotic tissue predominates. Ultrasound has been shown to demonstrate hypoechogencity of the EOM in active disease due to edema, whereas fibrotic muscle has irregularly high internal reflectivity. Although not commonly employed, color Doppler ultrasound demonstrates increased flow of the ophthalmic artery with active disease. Octreotide scans, also not commonly used due to lack of specificity, can reveal increased uptake in active/inflammatory muscle due to the increased expression of somatostatin by orbital lymphocytes, which are more active in the early phase of disease. Ultimately radiographic staging is secondary to clinical assessment in guiding treatment. Several classification systems exist, the two most widely used being VISA (vision, inflammation, strabismus, and appearance) and EUGOGO (European Group of Graves’ Orbitopathy).
Pathogenesis: In Depth
It is currently believed that orbital fibroblasts are the leading cell type responsible for thyroid orbitopathy’s distinctive orbital soft tissue transformations. Based on current evidence, factors such as the variable expression of cell-surface autoantigens and differences in inflammatory cytokine exposure account for differing phenotypes of thyroid orbitopathy. Current evidence shows that orbital fibroblasts express thyroid-stimulating hormone receptors (TSHRs), a physiologic antigen expressed on normal functional thyrocytes. TSH receptor autoantibodies (TRAbs) are thought to activate both thyrocytes (Graves) and orbital fibroblasts (TAO). In the final steps of the currently understood pathway, B cells produce TRAbs, which interact with TSHRs expressed on orbital fibroblasts and ultimately leads to orbital soft tissue swelling ( Fig. 39.5 ).
