The orbit resembles a rigid cone with its base open anteriorly, where it is bounded by the semidistensible anterior orbital septum. Edematous expansion of orbital tissue has predictable consequences: Dysfunction of affected muscles, increased orbital pressure, and proptosis (exophthalmos, forward displacement of the eye). The clinical expression relating to each of these factors depends on the site and severity of inflammation and the potential for forward displacement. Several extraocular muscles, including the levator palpebrae superioris, are usually affected, although with variable frequency (2,3). This may lead to restriction of eye movements, lid lag, and incomplete eyelid closure. The latter may provoke sight-threatening corneal exposure, often compounded by proptosis. The degree of proptosis is limited by the length of the rectus muscles and the tightness of the anterior orbital septum. If the muscles are unable to stretch and the septum is tight, proptosis is minimal, but orbital pressure and venous congestion increase, and the rectus muscles may then compress the optic nerve at the orbital apex, with resulting visual loss. Conversely, if the septum is lax and the muscles are able to stretch, then proptosis increases, occasionally allowing subluxation of the eyeball. Acute inflammation may also cause erythema and swelling of the conjunctivae and eyelids, compounded by venous and lymphatic congestion. Muscle inflammation gives way to fatty degeneration and scarring, sometimes with further tethering and restriction. Various stages of these processes may coexist in one or more muscle tissues.

The expansion of orbital tissues is primarily due to the edema that results from deposition of the very hydrophilic glycosaminoglycans. Orbital fibroblasts appear to synthesize and secrete these glycosaminoglycans in response to cytokines produced by infiltrating immune cells and macrophages and by the fibroblasts themselves (2,3). Cytokines also stimulate orbital fibroblasts, vascular endothelium, and macrophages to produce other immunomodulatory and inflammatory mediators. These in turn aid recruitment of T cells into the orbit and antigen recognition and presentation, and therefore perpetuate the local inflammatory response (2,3). A cell-mediated (Th1-type) immune response appears prominent early in the evolution of Graves’ ophthalmopathy, whereas humoral immunity (Th2-type), or both, may be relevant later in the course of the disease (2,3) and may be associated with fibrosis.

Evidence of autoimmune responses to thyroid antigens is invariably present in patients with Graves’ ophthalmopathy, including those with euthyroid Graves’ ophthalmopathy (2). An autoantigen shared by thyroid and orbit would explain the specific targeting of the latter and the close association between Graves’ thyroid disease and Graves’ eye disease. The most studied candidate autoantigen is the thyrotropin [thyroid-stimulating hormone (TSH)] receptor. This is expressed in orbital connective tissue, orbital fat (2,3), and extraocular muscle fibers (7), but at higher levels in patients with Graves’ ophthalmopathy than normal subjects (2,3). Orbital connective tissue contains adipocyte precursors (preadipocytes), which under appropriate conditions can differentiate into adipocytes (2,3). In vitro, expression of TSH receptors increases as fibroblasts differentiate to preadipocytes and adipocytes (2,3), and both differentiation and TSH-receptor expression are stimulated by cytokines (2,3). A central role for antibodies to the TSH receptor is also likely, by activating the fibroblast TSH receptor, leading to the differentiation of orbital fibroblasts into adipocytes (2,3), and thereby increasing orbital fat content (2,3). The absence of Graves’ orbitopathy in many patients with positive TSH-receptor antibodies suggests that other factors play a significant role in the pathogenesis of this disease. IGF-1 receptor expression in orbital fibroblasts from patients with Graves’ ophthalmopathy is increased compared to normal controls (7). Furthermore, the IGF-1 and TSH receptors appear to co-localize in orbital tissues from patients with Graves’ ophthalmopathy, and the two may form a functional complex (2). IGF-1 receptor expressing fibroblasts respond to IgGs from patients by producing chemoattractants (8). Circulating CD3 T cells from patients with Graves’ disease and some other autoimmune diseases also seem to express IGF-1 receptors (9). The role of these T cells in the pathogenesis of Graves’ ophthalmopathy is unknown but may support expansion of memory T cells. Circulating fibrocytes which express IGF-1 receptor and TSH receptor have been identified in much higher concentration in patients with Graves’ disease than in normal controls. (10). A concept is emerging that remodeling of connective tissue in the orbits and elsewhere may be driven by autoimmune processes and lead to the manifestations of Graves’ ophthalmopathy (3). IGF-1 and its receptor may represent an important switch, regulating the quality and amplitude of immune responses (2,3). The orbit may be constitutively primed to be metabolically more active than other tissues and therefore susceptible to inflammation (11). In the absence of a robust animal model, the precise roles of the TSH receptor, IGF-1 receptor, and effector cells remain at present elusive.

The genetic contribution to Graves’ disease is substantial. The same risks and associations apply to Graves’ ophthalmopathy (12). Several studies examining genes that may distinguish between patients with Graves’ disease with and without eye disease have focused on associations between ophthalmopathy and alleles at the major histocompatibility complex (MHC), cytotoxic lymphocyte-associated antigen-4 (CTLA-4), and other loci (13). These studies have yielded contradictory results, which may be partly due to differences in allelotyping methodology, disease definition, race/ethnicity of the study subjects, and small sample sizes. Other factors that are associated with severe eye disease include advanced age, male sex, smoking, and persistent thyroid dysfunction, particularly hypothyroidism (2,3,12).

Recommendations for objective assessment of Graves’ ophthalmopathy have been proposed (25), but there is no agreement as to precisely what to score and how to define it (22). A more detailed protocol with a soft-tissue atlas was published (22) and adopted by the European Group on Graves’ Ophthalmopathy (EUGOGO) (26); however, a further less detailed protocol has since been published in North America (27) and worldwide consensus remains elusive. Given the variable presentation of Graves’ ophthalmopathy, summary descriptions are of little use, and each feature should be assessed individually. The NOSPECS scheme (Table 18B.3) provides a useful mnemonic to assist this, although as a scoring system it has been justifiably criticized for poor definitions and reproducibility and for failing to record important change (22).

A complete examination protocol and photographic color atlas for the assessment of the soft-tissue changes that occur in patients with Graves’ ophthalmopathy can be found at http://www.eugogo.eu.

Widening of the palpebral fissure is usually due to retraction of both upper and lower eyelids and is caused by multiple factors (22). Upper-lid retraction probably relates mainly to levator and Müller’s muscle involvement plus tightness of the inferior rectus muscle, with smaller contributions from proptosis and scarring around the lacrimal gland fascia. Lower lid retraction correlates strongly with proptosis (Fig. 18B.3E). Standardized measurements require a consistent technique (distance fixation in a relaxed state, standardized head position, and, if vertical strabismus is present, occlusion of the contralateral eye). The width of the mid-pupil vertical fissure is measured, noting the distance between each lid and the adjacent limbus, plus the presence or absence of the upper-lid contour abnormality known as lateral flare (Fig. 18B.3D).