Graves Orbitopathy

Michael Kazim, MD

Introduction

Graves orbitopathy varies widely in its pattern of clinical presentation. Generalizations about the disease are not particularly useful when developing treatment plans for an individual patient, but the following description will serve as a starting point. Graves orbitopathy is identified in approximately 20% of patients presenting with Graves disease. A larger group manifests subclinical, self-limited forms of Graves orbitopathy. The prevalence of these milder forms of the disease is estimated to be as high as 80%. Graves orbitopathy commonly affects women in the fifth decade of life and is usually diagnosed soon after the hyperthyroid state appears. The self-limited disease requires only supportive measures except in cases where severe corneal exposure keratitis or compressive optic neuropathy threatens vision and requires immediate medical attention. The active phase of Graves orbitopathy typically lasts 1 year, following which most cases improve. Residual stigmata of the disease persist in most, but only a minority of patients require surgical rehabilitation.

Diagnostic Features

The diagnosis of Graves orbitopathy is based on the presence of characteristic clinical features, serologic studies, or radiographic findings.

Clinical Features
In 1969, Werner introduced the NOSPECS classification scheme for the signs and symptoms of Graves orbitopathy (Table 1). Although controversial as an index of disease severity, it serves well as a guide for the clinical features of the disease. Typically, patients will first complain of nonspecific symptoms that can mislead the clinician to a diagnosis of dry eye, allergies, viral conjunctivitis, contact lens intolerance, or a bug bite.

Table 1. Werner’s NOSPECS classification scheme.

Ultimately, the progression of periorbital swelling, appearance of lid retraction (especially the temporal upper eyelid) or proptosis, and development of diplopia calls into question earlier diagnoses. The clinical features are dependent, in part, on the age of the patient at the time of diagnosis. In the pediatric population, it is rare to identify eye signs or symptoms. However, when present, symptoms include proptosis and lid retraction, which may be reversible as the systemic disease is brought under control. It is uncommon to identify strabismus, and even less so optic neuropathy, in this age group. In 20- to 40-year-old patients, the eye disease is more common. It features proptosis and lid retraction that is not as reversible as in the pediatric group. These patients are more often spared the double vision and compressive optic neuropathy. From 40 to 65 years of age, the disease can manifest all the signs and symptoms included in Werner’s NOSPECS scheme. Strabismus and optic neuropathy become more frequent, while proptosis and lid retraction remain common features of the disease. In patients older than 65 years, proptosis and cutaneous edema and erythema are less common. This makes the clinical diagnosis of an elderly patient with new onset diplopia or vision loss more obscure.

Serologic Testing
The most useful blood test used to identify thyroid dysfunction is the thyroid-stimulating hormone level (TSH). A standard thyroid panel will generally include T4 and T3 levels. Suppression of the TSH level with an elevation of the T3 or T4 level in the absence of exogenous thyroid hormone supplementation is most commonly diagnostic of Graves disease. Additional testing may include an investigation for autoantibodies to thyroid proteins that are not universally identified and do not routinely correlate with disease activity.

Radiographic Testing
Noninvasive imaging is generally reserved for cases in which the diagnosis is uncertain based on clinical or serologic finding. Noninvasive imaging is also used to aid surgical planning or to exclude coexisting pathology. There are three modalities available — ultrasonography, computed tomography (CT), and magnetic resonance imaging (MRI).

Ultrasonography is an excellent screening test for cases in which Graves orbitopathy is suspected. It provides moderately good resolution in the anterior two-thirds of the orbit and can adequately identify muscle pathology in most cases. The test is fast and easy to perform in the office, but lacks the resolution and imaging of the posterior orbit that is required in some cases.

CT scanning is the gold standard for the diagnosis and treatment of Graves orbitopathy. Contrast enhancement is generally not required. CT provides information regarding the size and shape of the rectus muscles, excludes alternate or coexisting pathology, and examines the paraorbital sinuses.

MRI provides greater soft tissue detail but is lacking in bone resolution. Generally, MRI does not provide any clinical advantage in this disease. The classic CT finding is the fusiform enlargement of the rectus muscles, which spares the muscle tendons. The inferior and medial rectus muscles are the most commonly involved. Least common is the lateral rectus and oblique muscles. When the muscles enlarge markedly, the perioptic fat can be seen to be effaced, raising the possibility of compressive optic neuropathy. As mentioned previously, patients younger than 40 years old are more likely to suffer with proptosis and less so from strabismus and optic neuropathy. In such cases, the radiographic findings feature proptosis resulting from the expansion of the orbital fat compartment without significant enlargement of the extraocular muscles.

Pathophysiology

It is a widely held view that Graves orbitopathy is an autoimmune disease not directly related to thyroid hormone disregulation. As expected, improvement in the orbital disease does not routinely follow successful treatment of the dysthyroid state. However, evidence supporting an autoimmune etiology for Graves orbitopathy is largely circumstantial. Women are more likely to develop Graves disease and are up to eight times more likely to exhibit severe orbital involvement than men. Yet, among patients with Graves orbitopathy, men are more likely to develop optic neuropathy. The presence of the antibodies associated with thyroid enlargement and overactivity, termed thyroid-stimulating immunoglobulins, does not correlate routinely with the development of orbital disease.

The end-organ of the disease is also not well appreciated. However, evidence is mounting that the orbital fibroblast is the target of the disease. Unlike most other regions of the body, connective tissue investing the orbit contains fibroblasts derived from the neural crest. Neural crest-derived cells are unique in that they retain developmental plasticity long after gestation. Structures analogous to the fibrous septa in fat may exist in extraocular muscles in the form of the endomesium, perimesium, and epimesium. These sites are involved with intense scar formation in acute Graves orbitopathy, resulting in restrictive strabismus. Muscle fibers are relatively spared in Graves orbitopathy, suggesting that the connective tissue and not the extraocular muscle fiber represents the primary disease target.

The behavior of orbital fibroblasts in vitro has been studied exhaustively. Fibroblasts express surface receptor, gangliosides, and inflammatory genes. The in vitro behaviors of orbital fibroblasts suggest that they may play an active role in tissue remodeling and the local inflammatory responses. Unlike many other fibroblasts, those from the orbit display cell-surface CD40, a receptor initially found on B-lymphocytes and that is important to the activation of those cells. CD40 is activated by CD154, which is displayed on the surface of T lymphocytes. When CD40 on orbital fibroblasts is engaged by CD154, several inflammatory fibroblast genes are activated. IL-6 and IL-8 expression is dramatically upregulated, which, in turn, can result in enhanced chemotaxis of bone marrow derived inflammatory cells to the orbit. PCHS-2, the inflammatory cyclooxygenase, is induced by CD40 ligation on orbital fibroblasts. This induction results in substantial increases in the production of prostaglandin E₂. Fibroblast synthesis of hyaluronan, the glycosaminoglycan polymer thought to accumulate in the orbital connective tissue in Graves orbitopathy, is also increased by CD40 ligation. Many of the consequences of CD40 ligation in human fibroblasts can be attenuated with glucocorticoids.

Nonorbital fibroblasts fail to demonstrate as vigorous a response to inflammatory mediators, a fact that may explain the site-specific nature of the disease.

As a possible consequence of their neural crest origin, a subpopulation of orbital fibroblasts appears capable of undergoing adipocyte differentiation in vitro. This may account, in part, for the expansion of the orbital fat compartment seen in a subgroup of affected patients with proptosis and normal extraocular muscle size.

Cultured fibroblasts have been shown to increase the synthesis of glycosaminoglycan and collagen when subjected to low oxygen tension. Orbital ischemia may result from obstruction of venous and, perhaps, lymphatic outflow. The mechanism of the production of orbital ischemia in Graves orbitopathy is debated. It may be argued that orbital ischemia plays a role in the disease and that maneuvers to improve orbital blood flow are beneficial. Among these are the cessation of smoking which reduces oxygen tension in all tissues and has been shown to have a promoting effect on the disease in women.

Management

The management of a Graves orbitopathy is tailored to the individual patient. Treatment is guided by the age of the patient, the activity of the orbital disease, the clinical features, and the severity of the process.

Thyroid
While highly controversial, some consideration should be given to the role of thyroid treatment on the activity of the orbitopathy. There are three forms of treatment available for hyperthyroidism. First are the thyroid suppressor drugs, including propothiouracil and Tapazole (methimazole, Jones Pharma). These medications are prescribed with the anticipation that the disease will either remit spontaneously as it does in approximately 20% of cases or more definitive treatment will follow. In the United States, Canada, and the United Kingdom, traditionally, the majority of patients with Graves hyperthyroidism are treated with radioactive iodine (RAI). In continental Europe, the favored treatment is thyroidectomy. In recent years, RAI has come under scrutiny as a promoter of the orbital disease. However, all studies have failed to confirm this notion, due to unfortunate flawed study design. It is important to bear in mind that the orbitopathy occurs within 18 months of identification of the hyperthyroid state in 80% of patients and can predate hyperthyroidism.

A recent study suggested that patients with active and severe Graves orbitopathy are at greater risk of exacerbating the orbitopathy if the hyperthyroid state is treated with RAI than with medications or surgery. Of note, at the conclusion of the study those patients who required prednisone treatment for the worsened orbitopathy did not have a significantly different severity index than the group that did not receive RAI.

Based on the current data, several recommendations regarding thyroid treatment can be made. Patients should be rendered euthyroid as rapidly as possible and thyroid levels should not be allowed to fluctuate widely. Treatment of the hyperthyroid state is at the discretion of the endocrinologist without clear association with the development of the orbital disease. In patients with active, severe, rapidly progressive orbitopathy with optic neuropathy, RAI should be avoided, delayed, or used along with oral prednisone. For patients with mild or nonexistent orbitopathy, the concomitant use of prednisone with RAI is used on only theoretical grounds.

Acute Phase Orbitopathy
The acute, inflammatory phase of Graves orbitopathy can, in some cases, be difficult to identify. However, it generally features variable edema and erythema of the periorbital skin. During the acute phase, measurements of proptosis, strabismus, eyelid retraction, and optic neuropathy can be expected to worsen and then ultimately improve over 6 months to 2 years. Supportive medical measures include topical lubricants, wrap around sun glasses, punctum plugs, limited salt intake, head elevation at bedtime, and Fresnel prism lenses. More aggressive medical therapy is reserved for cases of optic neuropathy and patients with rapidly progressive disease. In such cases, treatment options include corticosteroids, orbital radiotherapy, and surgical orbital decompression.

At our institution, we have had success using orbital radiotherapy in this subgroup of patients unless contraindicated by the coexistence of vasculitis or juvenile diabetes. Generally, patients receive oral corticosteroids during the 2-week course of radiotherapy. After completion of the 2,000 cGy treatment, the steroids are tapered as rapidly as tolerated to preserve optic nerve function. The full therapeutic effect of the radiotherapy is appreciated within 3 months in 80% of patients, and in 90% over the course of 6 months following the completion of treatment. When orbital radiotherapy fails to resolve the optic neuropathy or is contraindicated, surgical decompression in the acute phase is recommended. Removal of all four orbital walls has been described. In cases of compressive optic neuropathy, we currently recommend a balanced lateral wall decompression combined with an endoscopic medial decompression.

Stable Phase Orbitopathy
The stable phase of Graves orbitopathy is characterized by an absence of progression or improvement in the clinical signs or symptoms. During this phase, rehabilitative surgical procedures are performed on an elective basis. When indicated, the first procedure is surgical decompression. Strabismus surgery and lid surgery to correct eyelid retraction follow with typical intervals of 6 to 8 weeks. In the stable phase, the choice of surgical decompression is based on a review of the orbital CT or MRI and predisease facial photographs. Using the scans, an estimate is made of the relative contribution of the extraocular muscle volume to the proptosis. We have divided the patients into three groups. The first group has normal-sized extraocular muscles. In this group, proptosis results from an expansion of the orbital fat compartment. Scans performed for the second group show markedly enlarged rectus muscles which produce the proptosis. The last group has proptosis resulting form a combination of moderately enlarged rectus muscles and expanded orbital fat. Decompression by orbital fat removal has resulted in an average of 3 mm and as much as 6 mm reduction in proptosis in the first group. The group with markedly enlarged extraocular muscles benefits from a bone decompression in which we routinely remove both the lateral and medial orbital walls and anticipate an average reduction of 5 mm to 6 mm in proptosis. Currently, removal of the floor and roof is reserved for patients who desire greater reductions in proptosis. If 3 mm of proptosis is desired, then a combined fat and lateral wall decompression is also useful in cases of proptosis asymmetry of more than 3 mm. When a more substantial reduction in proptosis is desired, or in cases in which the result of a prior fat decompression is inadequate, a balanced medial and lateral wall decompression is performed.

If a patient suffers with diplopia following decompression, strabismus surgery is performed. Muscle recessions are the rule, guided by preoperative orthoptics measurements and intraoperative forced duction tests to determine which muscles are to be operated on and the amount of recession. In some cases, adjustable sutures can be of value. The final results are appreciated in 6 to 8 weeks.

Lid retraction can occur in both the upper and lower eyelids. In the case of the lower eyelids, a conjunctival approach is used to recess the conjunctiva and lid retractors as complex. Following this, an interpositional graft is placed between the cut ends. The most frequently used grafts for this application are oral mucosa and free tarsoconjunctiva from the upper eyelid. Upper eyelid retraction repair varies based on the degree of retraction. When the retraction is limited to 3 mm, a transconjunctival resection of the Müller muscle can be performed in a graded fashion under local anesthesia. When the retraction is more than 3 mm, or when there is severe lateral retraction, an external approach to a graded recession of the levator and Müller muscle is performed. The reoperation rate for lid height or contour asymmetry is between 10% and 20%. Skin resection in either the upper or lower lids is performed conservatively in this group of patients, but anterior orbital fat may be removed at the time of the lid retraction repair if not previously performed as a part of the orbital decompression.

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