Pathophysiology

Extensive research in recent years has led to important insights into the pathologic mechanisms involved in Graves’ disease and Graves’ ophthalmopathy. As understanding progresses, so should the ability to deal with this challenging disorder.

Graves’ Disease

Current theory describing the development of Graves’ disease involves autoreactive T cells, which arise through an escape from clonal deletion, through failure of suppressor T-cell activity, or through molecular mimicry to become reactive to TSH receptors.^6,⁷ Most of the T cells responsible for the reaction are located in the thyroid gland itself. Subsequent thyroid damage from any etiology (e.g., chronic thyroiditis, radiotherapy, smoking, drugs) results in the release of the thyroid autoantigen (TSH receptors). As the autoimmune process amplifies, T lymphocytes are activated, and humoral immunity produces antibodies to the TSH receptor that are stimulatory, resulting in hyperthyroidism. In some patients, underlying chronic thyroiditis may dramatically reduce thyroid reserve, or TSH receptor–blocking antibodies may be present, resulting in “euthyroid” patients with Graves’ disease.

Graves’ Ophthalmopathy

The extraocular muscles are the site of the most clinically evident changes in patients with Graves’ ophthalmopathy. Although the muscles are enlarged on computed tomography (CT) scan, the myocytes themselves appear fairly normal histopathologically.⁸ There is an associated intense proliferation of perimysial fibroblasts and dense lymphocytic infiltration. Early reports of circulating autoantibodies against eye muscle antigen in sera from patients with Graves’ ophthalmopathy led to the theory that the disease was a result of an autoimmune response directed against the extraocular eye muscle fibers.⁹ This theory began to lose favor as study of these autoantibodies proved them to be neither tissue-specific nor disease-specific. The lack of histologic evidence of cytotoxicity against eye muscle in vivo also argues against this theory.

Attention has now focused on the retrobulbar fibroblast as playing a key role in the pathogenesis of Graves’ ophthalmopathy. These fibroblasts have several capabilities that place them at the center of the changes seen in the eye. They secrete a range of glycosaminoglycans (predominantly hyaluronate), the deposition of which is a hallmark of Graves’ ophthalmopathy and causes interstitial edema as a result of their intensely hydrophilic nature. These cells can also produce major histocompatibility complex (MHC) class II molecules, heat shock proteins, and lymphocyte adhesion molecules, which allow them to act as target and effector cells in the ongoing immune process in patients with Graves’ ophthalmopathy.¹⁰ In addition, autoantibodies against fibroblast antigens have been found in most patients with Graves’ ophthalmopathy. These antibodies share some characteristics with TSH receptor antibodies (TRAbs).⁵ More recently, probes to TSH receptor messenger RNA (mRNA) have labeled mRNA within the retrobulbar fibroblasts of patients with Graves’ ophthalmopathy.⁶ The “fibroblast antigen” may be similar to all or part of the TSH receptor, and it represents a shared thyroid-eye antigen. Such an antigenic similarity would explain the immune cross-reactivity between these two seemingly unrelated tissue sites.

Lymphocytes also are active in the ongoing immune process of Graves’ ophthalmopathy. Orbital lymphocyte infiltrates have been found to be primarily T cells, including CD4⁺ (T helper cells) and CD8⁺ (T suppressor and cytotoxic cells). Cytokines released by T cells have been shown to induce fibroblast proliferation and collagen and glycosaminoglycan deposition. Grubeck-Loebenstein and colleagues ¹¹ cultured retrobulbar suppressor and cytotoxic T cells out of tissues removed at the time of orbital decompression, and found them capable of targeting the retrobulbar fibroblasts. Interactions with fibroblasts resulted in pronounced T-cell cytokine production and fibroblast proliferation without evidence of fibroblast cytotoxicity. The T cell–retrobulbar fibroblast interaction may be responsible for the clinical manifestations of Graves’ ophthalmopathy.

Epidemiology and Etiology

An accurate estimate of the prevalence of Graves’ ophthalmopathy is difficult to determine and depends in part on the diagnostic criteria used to define the presence of ophthalmopathy. “Lid lag” and “stare” are nonspecific signs and can be seen with thyrotoxicosis stemming from etiologies other than Graves’ disease. In an exhaustive review of the literature, Burch and Wartofsky ⁶ found an incidence of ophthalmopathy in patients with Graves’ disease of 10% to 25% if these nonspecific signs were excluded, and 30% to 45% if lid findings were included as diagnostic criteria. When intraocular pressure on upgaze or CT findings also were included, the incidence increased to nearly 70%. The most severe form of Graves’ ophthalmopathy with optic nerve involvement and visual impairment occurs in only 2% to 5% of patients with Graves’ disease.^12,¹³

Effects of Genetics and Sex

The role of genetic predisposition and MHC antigen patterns in patients with Graves’ ophthalmopathy has been extensively studied, but remains poorly characterized.⁶ Ethnicity seems to play some role; Tellez and coworkers¹⁴ found that European patients with Graves’ disease were six times more likely to develop ophthalmopathy than Asian patients with Graves’ disease. More important are the influences of sex on the development of Graves’ disease and the associated ophthalmopathy. A strong 3 : 1 female-to-male preponderance exists for Graves’ disease,^15,¹⁶ which decreases to about 2 : 1 for patients with Graves’ ophthalmopathy. Overall, male patients with Graves’ disease have a higher incidence of ophthalmopathy that is more severe and tends to develop later in life.⁶

Effects of Tobacco

Several studies have reported an increased incidence of goiter in tobacco smokers compared with nonsmokers, attributing this to thiocyanate, a known goitrogen that is present in inhaled tobacco smoke.^17,¹⁸ Studies have also reported an association between smoking and the incidence and severity of Graves’ ophthalmopathy.^14,¹⁹ This relationship was not found in patients with other forms of thyroid disease, and suggests the tobacco effects are specific to Graves’ disease. It is possible that the decrease in female preponderance in Graves’ ophthalmopathy, especially in the more severe forms, may be a reflection of the higher incidence of smoking among male patients, rather than a true sex difference.⁶

Effects of Thyroid Status

The role of thyroid hormonal status in the development and severity of Graves’ ophthalmopathy has been particularly difficult to ascertain because of the overlap of thyrotoxicosis with antithyroid therapy in these patients. Thyrotoxicosis alone is thought to have little direct effect on the autoimmune process. It serves as a poor marker for disease severity because the prevalence and course of hyperthyroidism correlate poorly with that of Graves’ ophthalmopathy.⁶ An improvement in eye status with maintenance of euthyroidism during antithyroid therapy may be more a reflection of improving immune function than a decreased circulating thyroid hormone.

Elevated circulating TSH levels seem to promote eye disease in patients with Graves’ disease. Hamilton and colleagues ²⁰ have reported an increased incidence of progressive ophthalmopathy with hypothyroidism, which followed antithyroid therapy. Tamaki and associates²¹ described a marked improvement in eye status and a reduction of circulating TRAb in two patients receiving thyroid hormone replacement during antithyroid therapy. The mechanism by which elevated TSH achieves its influence is unclear, but it may serve to up-regulate TSH receptors (apparent autoantigens; discussed later) in thyrocytes²² and possibly lymphocytes.²³

Natural History

On summarizing the available literature on the natural history of Graves’ ophthalmopathy, Burch and Wartofsky ⁶ noted the disease tended to progress through a phase of rapid progression (6 to 24 months), followed by a prolonged plateau phase with subsequent slow but incomplete regression of eye changes. Lid retraction and soft tissue changes, such as chemosis and eyelid edema, tended to be short-lived with improvement or resolution over 1 to 5 years (60% to 90%). Ophthalmoplegia resolved incompletely and less rapidly, although 30% to 40% of patients showed some improvement in ocular motility without specific therapy. Proptosis is the eye finding least likely to improve or resolve spontaneously (10%). Trobe²⁴ reviewed 32 patients with untreated Graves’ optic neuropathy and found that vision improved spontaneously in most, but 21% had a final visual acuity of 20/100 or worse, with 5 patients progressing to near blindness. Facing potential loss of sight, it is not surprising that attempts at medical and surgical intervention, some of them heroic, have occurred for the past 80 years.

Clinical Features

Thyroid Disease

A patient with Graves’ ophthalmopathy most commonly visits an endocrinologist for management of thyroid disease or an ophthalmologist for evaluation of eye complaints. A thorough history, examination, and high level of suspicion are required to make the diagnosis. Classically, the patient is experiencing hyperthyroidism, and the expected hypermetabolic findings are present at the time of presentation with eye disease. In a review of more than 800 cases from the literature, Burch and Wartofsky ⁶ found, however, that 20% of patients presented with eye disease before any manifestation of hyperthyroidism, 39% presented concurrently with thyroid disease and eye disease, and 41% presented with eye disease after clinical hyperthyroidism already was evident. In 80% of the patients in whom both diseases eventually manifested, both became clinically evident within 18 months of each other, although some patients may never present with thyroid disease and eye disease, or many years may separate the two presentations.

Pretibial Myxedema

Pretibial myxedema, or thyroid dermopathy, is the localized thickening of the skin, usually in the pretibial area. It occurs in 4.3% of patients with Graves’ disease, but at a higher rate (12% to 15%) in patients with Graves’ ophthalmopathy,^25,²⁶ and usually is a late manifestation. Conversely, almost all patients with pretibial myxedema have Graves’ ophthalmopathy, although the dermopathy may precede the ophthalmopathy. Symptomatic lesions consist of shiny, erythematous-to-brown plaques, nodules, or areas of nonpitting edema, which most commonly occur in the anterior or lateral aspects of the leg or at sites of old or recent trauma. Involvement of other body sites is rare. Almost all patients have high circulating levels of TRAbs, although the true pathogenesis of the dermopathy is not understood. Pretibial myxedema usually is of cosmetic importance only, but if the feet or hands become massively swollen, it can cause functional difficulties.

Graves’ Ophthalmopathy

As described previously, Graves’ disease occurs more commonly in women and over a broad age range (16 to 81 years), with a mean age in the fifth and sixth decades.²⁷^–²⁹ Eye involvement is bilateral in most patients with Graves’ disease, although 5% to 14% of patients have unilateral disease depending on the method of detection.⁶ With careful testing (i.e., CT scan), 50% to 90% of these patients show changes in both eyes. In contrast, major asymmetry in the extent of eye involvement is common. Graves’ ophthalmopathy remains the most common etiology of “unilateral” proptosis in adults.³⁰

Ophthalmopathy Classification

The spectrum of eye changes ranges from eyelid retraction (resulting in the appearance of a “stare”), to proptosis, corneal exposure and ulceration, diplopia, and loss of vision. A clinical classification system for eye involvement by Graves’ disease was proposed by Werner in 1969,³¹ approved by the American Thyroid Association (ATA), and subsequently modified in 1977.³² The ATA’s detailed classification is shown in Table 126-1. This classification is strictly clinical and has been helpful for reporting purposes. The disease does not progress systematically through the classes, and may skip one or more classes entirely. In addition, the classification system has been criticized for not considering disease activity (stable or rapidly progressing), which is crucial for making patient treatment decisions.³³

Table 126-1 Detailed Classification of Eye Changes of Graves’ Disease

Classes	Grades	Ocular Symptoms and Signs
0		No signs or symptoms
I		Only signs, no symptoms (signs limited to upper lid retraction and stare, with or without lid lag and proptosis)
II		Soft tissue involvement with symptoms and signs
	o	Absent
	a	Minimal
	b	Moderate
	c	Marked
III		Proptosis ≥3 mm in excess of upper normal limit, with or without symptoms
	o	Absent
	a	3- to 4-mm increase over upper normal
	b	5- to 7-mm increase
	c	≥8 mm increase
IV		Extraocular muscle involvement (usually with diplopia, other symptoms or signs)
	o	Absent
	a	Limitation of motion at extremes of gaze
	b	Evident restriction of motion
	c	Fixation of a globe or globes
V		Corneal involvement (primarily a result of lagophthalmos)
	o	Absent
	a	Stippling of cornea
	b	Ulceration
	c	Clouding, necrosis, perforation
VI		Sight loss (caused by optic nerve involvement)
	o	Absent
	a	Disk pallor or choking, or visual field defect: vision 20/20 to 20/60
	b	Same, but vision 20/70 to 20/200
	c	Blindness (i.e., failure to perceive light, vision <20/200)

In response to these deficiencies and several other proposed classification schemes, an international ad hoc committee representing the American, European, Asia-Oceanic, and Latin America Thyroid Associations recommended in 1992 a new characterization of Graves’ ophthalmopathy (Table 126-2). This system is recommended for use in attempting objective clinical assessment and documenting disease activity, as in clinical studies. The older ATA classification system is still used for educational purposes and clinical evaluation.

Table 126-2 Characterization of Graves’ Ophthalmopathy: Recommendations of an International Ad Hoc Committee *

Category of Disease	Objective Criteria Monitored
Eyelid	Maximal lid fissure width
	Upper lid to limbus distance
	Lower lid to limbus distance
Cornea	Exposure keratitis assessed by rose bengal or fluorescein staining (indicate presence or absence)
Extraocular muscles	Single binocular vision in central 30 degrees of vision (indicate presence or absence, with or without prisms)
	One or more of the following measurement techniques
	Maddox rod test
	Alternate cover test
	Hess chart measurements
	Lancaster red-green test
	Optional
	Intraocular pressure in downward gaze
	CT or MRI
Proptosis	Exophthalmometer reading (CT or MRI measurement may also be used for measurement)
Optic nerve	Visual acuity
	Visual fields
	Color vision
Activity score	Sum of 1 point each for any of the following
	Spontaneous retrobulbar pain
	Pain with eye movement
	Eyelid erythema
	Eyelid edema or swelling
	Conjunctival injection
	Chemosis
	Caruncle swelling
Patient self-assessment	Satisfaction with the following (indicate change with therapy in each using a scale such as greatly improved, improved, unchanged, worse, much worse)
	Appearance
	Visual acuity
	Eye discomfort
	Diplopia

* Consensus of an 18-member ad hoc committee comprising representatives from the American, European, Asia-Oceanic, and Latin America Thyroid Associations.

From Classification of eye changes of Graves’ disease. Thyroid. 1992;2:235.

Eye Findings

Lid lag and the appearance of a stare are seen in the mildest form (ATA class I disease) of eye involvement by Graves’ disease. This involvement is thought to occur initially as the result of an increased sympathetic sensitivity to catecholamines as seen with patients with hyperthyroidism.³⁴ As the disease progresses, and the lymphocytic inflammatory reaction infiltrates the extraocular muscles and orbital fat, the fibroblasts proliferate and deposit glycosaminoglycans, predominantly hyaluronic acid.^35,³⁶ The resulting muscle and fat enlargement combines with interstitial edema to cause an increase in intraocular pressure.

Intraocular pressure is increased in primary gaze (straight ahead) and even more so in upward gaze (supraduction). This increase in intraocular pressure can lead to a misdiagnosis of glaucoma, with a subsequent delay in appropriate therapy.²⁸ Over time, increases in intraocular pressure also produce conjunctival chemosis, excessive lacrimation, periorbital edema, and photophobia (ATA class II disease).

As enlargement of orbital muscle and fat progresses, the volume of the orbital contents increases. The orbital cavity has four fixed bony walls with an average volume of 26 mL.³⁷ In healthy individuals, the globe takes up 30% of this volume, with retrobulbar and peribulbar structures taking up the remaining 70% of the volume. With nowhere else to expand, an increase of only 4 mL in the volume of the orbital contents results in 6 mm of proptosis (ATA class III disease).

As the extraocular muscles become increasingly enlarged by edema and infiltration, they also become dysfunctional, resulting in reduced ocular mobility and diplopia (ATA class IV disease). Over time, the inflammatory response provokes the deposition of collagen by the fibroblasts, replacing the normally elastic muscles of the eye and ultimately causing a permanent fibrotic, restrictive ophthalmoplegia.

Progressive proptosis also dramatically interferes with the protective mechanisms of the cornea, causing exposure, desiccation, irritation, and, ultimately, ulceration (ATA class V disease). Corneal ulceration becomes a vision-threatening problem, with a risk of permanent corneal scarring, and requires immediate attention.

In its most severe form, Graves’ ophthalmopathy involves the optic nerve to impair vision (ATA class VI disease). Optic nerve involvement typically manifests as a painless gradual loss of visual acuity or visual field,¹² although it can occur precipitously over days to weeks. Although originally thought to be caused by ischemia or venous congestion of the nerve as a result of increased intraocular pressure, there now is convincing evidence to support crowding and compression of the optic nerve at the orbital apex by the enlarged extraocular muscles as the etiology of nerve dysfunction.³⁸

Optic nerve function is measured in several ways, one or all of which may be impaired. In one study of 31 patients with optic nerve involvement,²⁸ visual acuity was 20/25 or worse in 100% of eyes; color vision was decreased in 64%; and visual fields were decreased in 70%, with inferior scotomata and cecocentral scotomata defects most common. Impaired visual fields or color vision also may be found in patients with normal visual acuity.²⁷