Ординатура / Офтальмология / Английские материалы / Clinical Medicine in Optometric Practice_Muchnick_2007

134 CLINICAL MEDICINE IN OPTOMETRIC PRACTICE

plasmapheresis, radiation therapy, orbital decompression, and corrective eye surgery.

Thyroid Disease

Graves’ disease may occur independently of thyroid disease (so-called Graves’ euthyroid orbitopathy), but the ophthalmopathy occurs mostly in patients with hyperthyroidism. It is clear, therefore, that these two conditions share some pathophysiologic relationship and that an understanding of thyroid disease is necessary to study the pathogenic mechanism behind EO.

Thyroid Physiology

A sensitive feedback loop exists to regulate the level of serum thyroid hormones. This modulating system is known as the hypothalamic-pituitary thyroid axis. The basal hypothalamus located in the lateral wall of the third ventricle contains nerve endings that release thyroid-releasing hormone (TRH), a tripeptide. TRH stimulates thyroid-stimulating hormone (TSH) secretion from the pituitary gland. A polypeptide, TSH is the primary agent stimulating the thyroid gland to produce two metabolically active hormones: triiodothyronine (T3) and thyroxine (T4). Elevated levels of T3 (three iodide atoms) and T4 (four iodide atoms) in turn exert a negative feedback at the level of the pituitary gland, thus reducing TSH production. Therefore, TSH is controlled by both the hypothalamic hormone TRH and the thyroid hormones T3 and T4.

Thyroid Function Tests

Three types of thyroid function tests exist: serum thyroid hormone tests, hypothalamic pituitary-thyroid axis tests, and direct thyroid function tests. The serum thyroid hormone tests include serum T4, serum T3, serum free T4 and T3, T3 resin uptake, and free T4 index.

Serum thyroid hormone tests analyze T4 and T3 by radioimmunoassay, which measures the total bound and unbound fractions of each. The unbound (free) levels more accurately reflect the metabolic state than do the bound levels. The normal T4 1evel is 4 to 12 µg/dl, and the normal T3 level is 75 to 195 µg/dl. Hyperthyroidism and hypothyroidism produce changes in serum levels of T3 and T4 detected in these tests. The T4 is the standard screening procedure for diagnosing hyperthyroidism and hypothyroidism.

Another serum thyroid hormone test is serum-free T4 and T3, but it is difficult to perform and expensive to measure these free hormones directly. The serum thyroid hormone test most commonly used to evaluate thyroid binding is the T3 resin uptake (T3RU). This test does not measure circulating T3. Instead, the patient’s serum is incubated with a T3 tracer (radioiodinelabeled T3) and an insoluble resin to bind the remaining free T3. The T3 tracer has a greater affinity for the available serum binding sites, thus after incubation the

fraction of the labeled T3 absorbed on the resin is determined. What is actually measured is the amount of radioactivity bound on the resin. The T3RU is low in hypothyroidism and high in hyperthyroidism. The normal T3RU is 25% to 35%. The free T4 index is a mathematical computation involving the total serum T4 and T3RU, and it provides a good approximation of free T4 (normal free T4 index 1 to 4).

The hypothalamic-pituitary-thyroid axis tests include the serum TSH, the TRH test, and T3 suppression test. The serum thyrotropin (TSH) level is measured by radioimmunoassay, and normal is less than 7 µU/ml. If elevated, hypothyroidism is suspected. Serum TSH is not of value in determining hyperthyroidism, because most assays are not sensitive enough to distinguish normal from low levels. A new and very sensitive double-antibody technique for measuring below normal TSH levels has been developed, however. The TSH immunoradiometric assay (TSHIRMA) can detect low TSH levels, indicating mild hyperthyroidism.

The TRH stimulation test determines how well the pituitary can secrete TSH in response to an intravenous injection of 200 to 500 mg of TRH. A normal TSH response to TRH excludes hyperthyroidism. An abnormally low response of TSH to TRH indicates hyperthyroidism, and an exaggerated TSH response reflects hypothyroidism.

The T3 suppression test (Cytomel) is a radioactive iodine-uptake (RAIU) test performed before and after injection of T3, 3 times daily for 10 days. A comparison is then made of the two RAIU readings. Normally, the RAIU level is reduced to less than half during the 10-day period. If this reduction occurs, then hyperthyroidism is ruled out. The T3 suppression test has been largely supplanted by the TRH stimulation test.

A direct test of thyroid function is the radioactive iodine uptake (RAIU) test. Radioisotope is injected and competes with stable iodine. This test is limited in its diagnostic uses and is now of primary value in the T3 suppression test.

The eye care specialist who encounters a patient with suspected EO should have T3 and T4 levels run. If T3 and T4 are normal, then the hypothalamic pituitary-thyroid axis should be tested by a TRH stimulation test or by the more sensitive TSH-IRMA test. The TSH-IRMA may be more sensitive in diagnosing the so-called Graves’ euthyroid patient. The optometrist should consult with an endocrinologist who specializes in thyroid disease for any patient suspected of having EO.

Abnormal Thyroid Function

Hyperthyroidism. The term hyperthyroidism, first used in 1907 by Mayo, describes an abnormal state produced by elevated serum thyroid hormone levels.

The most common cause of hyperthyroidism is Graves’ disease, which was first recognized and described by Parry in 1825. The cause of the hyperthyroidism in Graves’ disease is an autoimmune disorder that results in the formation of thyroid-stimulating immunoglobulins. These immunoglobulins are antibodies most likely directed against the thyroid cell receptor, where they mimic TSH and cause the thyroid to overproduce and release thyroid hormones. The result of Graves’ disease is a diffuse goiter with infiltrative ophthalmopathy and, on occasion, an infiltrative dermopathy of flesh-colored papules on the shin known as pretibial myxedema.

The most common symptom of hyperthyroidism (Box 12-2) is excessive nervousness, accompanied by insomnia, hyperactivity, and palpitations. Patients usually note that they have lost weight despite an increase in appetite. A cessation of menstrual flow may occur. The patient may notice tremors of the digits, heat intolerance, fatigue, and weakness.

Significant clinical signs of hyperthyroidism include a prominent stare secondary to retraction of the upper lid, sinus tachycardia, goiter, thyroid bruit, hyperactive deep tendon reflexes, and vitiligo in 10% of patients. The course of the disease is varied, and the goiter may remit and spontaneously reoccur years after treatment.

The diagnosis of hyperthyroidism (Box 12-3) is made on the basis of clinical suspicion of patients who exhibit any of the above signs and symptoms, a significant history, physical examination, and laboratory testing. In most cases of hyperthyroidism the free T4 index is elevated and establishes the diagnosis in a likely suspect. If a patient is suspected of having a

BOX 12-2

SYMPTOMS OF HYPERTHYROIDISM

Major symptoms

Nervousness

Hyperactivity

Insomnia

Swings of emotion

Common symptoms

Heat intolerance

Excessive perspiration

Palpitations

Increased appetite

Weight loss

Diminished menstrual flow

Muscle weakness

Occasional symptoms

Anorexia

Nausea

Vomiting

Dyspnea

BOX 12-3

PREDISPOSITIONS OF GRAVES’ DISEASE

Familial predisposition

Most frequent ages: 25 to 50 years.

Ten times more common in women than men.

hyperthyroid state but the free T4 index is normal, then a serum T3 measurement should be obtained. If abnormal, this condition is called T3 thyrotoxicosis.

Three therapeutic strategies are available at present for the treatment of hyperthyroidism: drug treatment, radioiodine therapy, and surgery. Methimazole (Tapazole) and propylthiouracil (PTU) act to block the synthesis of thyroid hormones and have immunosuppressive effects. Neither drug causes permanent hypothyroidism, and treatment usually lasts a total of 12 to 18 months. In the first 3 months the serum thyroid hormone levels usually drop to a euthyroid level. These medications have some significant side effects. Antithyroid medications are advised for children and young adults or patients with small goiters and mild symptoms.

Potassium iodine has been used as a valuable adjunct to radiation therapy by blocking release of hormone from the thyroid gland. Beta-blockers have been used to reduce the hyperactive states associated with hyperthyroidism.

Adults older than 40 with hyperthyroidism should receive radioactive iodine therapy. Full amelioration of the symptoms and signs and a return to a euthyroid state occur in 75% of patients 2 to 6 months after administration of radioactive iodine. Within the first year of treatment, 15% to 20% of all patients develop hypothyroidism. Therefore, all patients undergoing radioactive iodine treatment should be made aware of the signs and symptoms of hypothyroidism.

Surgery is considered only rarely in the management of hyperthyroidism. Children and young adults should have antithyroid drug therapy before inadequate control forces a surgical decision. Patients who decline radiation therapy or who have large goiters may be candidates for surgery. Some evidence exists that thyroidectomy (near total removal of the thyroid gland) has a positive effect on EO, but not enough studies have been done to confirm this.

Hypothyroidism. If an insufficient amount of thyroid hormone results in a reduced metabolic state, then a state of hypothyroidism exists. The most common cause of hypothyroidism is Hashimoto’s thyroiditis. As mentioned previously, treatment of hyperthyroidism by radioactive iodine or thyroidectomy may result in hypothyroidism.

Hypothyroidism has few early symptoms and may exist as a subclinical entity for many years before being

136 CLINICAL MEDICINE IN OPTOMETRIC PRACTICE

diagnosed. Patients have few symptoms beyond cold intolerance, peripheral paresthesias, and complaints of bloating. Hypothyroidism is diagnosed by the laboratory finding of a low free T4 index. Unfortunately, the free T4 index may be normal in mild hypothyroidism. The most sensitive laboratory indicator for hypothyroidism is an elevated serum TSH level (in spite of a normal T4 index). Serum T3 is not a sensitive indicator of hypothyroidism.

Hypothyroidism is readily treated with the use of L-thyroxine to restore normal circulating thyroid hormones. The serum TSH assay can be used to precisely adjust thyroid replacement therapy to optimize the level of circulating hormones.

Hashimoto’s Thyroiditis. Thyroiditis is an inflammation of the thyroid gland, and several forms exist based on cause and pathology. Hashimoto’s thyroiditis is the most common thyroid disease and the most common cause of goiter in the United States, and the most common of all autoimmune diseases.

Patients usually experience the subtle signs and symptoms of hypothyroidism with a diffuse, nonpainful, firm, and asymmetric goiter. Laboratory testing confirms the diagnosis of Hashimoto’s thyroiditis. Treatment is the same as for hypothyroidism, in that administration of L-thyroxine inhibits TSH secretion and causes goiter regression. Patients sometimes receive treatment for life.

Endocrine Ophthalmopathy

Pathogenesis

For as yet unknown reasons, antibodies called thyroidstimulating immunoglobulins are directed against the TSH receptor on the thyroid gland. HLA-DR antigens on certain cells of the thyroid may facilitate the action of these antibodies. Some evidence indicates that perhaps a bacterial or viral infection stimulates antibody production against the invading organism but that these immunoglobulins cross-react with the thyroid TSH receptor. These antibodies mimic TSH activity, causing hormonal overproduction that yields a hyperthyroid state.

The autoimmune aspects of EO are less clear. The thyroid has been established as the target site of thyroid-stimulating antibodies, and EO has been established as an autoimmune disease most frequently associated with hyperthyroidism, but the biochemical and immunologic links between the two remain largely unexplored. This fact is the result of a lack of retroorbital tissues of patients with EO available for study. Many laboratory approaches are currently used to study the established fact that autoantibodies (T lymphocytes) are reacting against retro-orbital tissues. Such studies indicate that the eye muscles and surrounding connective tissue are the target of the autoimmune response, but the antigen for this reaction and

the immunopathologic processes occurring in the orbit have not been established.

One theory that links the autoimmune nature of thyroid disease with the histologic changes in the swollen extraocular muscles suggests the presence of a cross-reactive antigen within the thyroid and the orbit. One study suggests that T cells (autoantibodies) are sensitized to orbital antigens in patients with EO. If this is the case, autoantibodies could become sensitized to orbital tissues, and these T cells could infiltrate the muscle, releasing cytokines that activate fibroblasts. It has been firmly established that these autoantibodies react with fibroblasts. The fibroblasts produce glycosaminoglycans (GAGs), which cause swelling and fibrosis of the extraocular muscles. GAGs are molecules that induce edema. This muscular edema is rich in mucopolysaccharides, and thus research efforts are currently focused on autoantibodies with cell-stimulating properties. The autoantibodies to eye muscles in patients with EO can be detected by enzyme-linked immunosorbent assay testing (ELISA), but the detection rate is less than 60%.

Diagnostic Tests and Clinical Techniques

Clinical Signs and Symptoms. In endocrine ophthalmopathy an infiltration of the extraocular muscles with chronic inflammatory cells, associated with edema and fibrosis of the connective and adipose tissue of the orbit, causes an enlargement of the retrobulbar contents leading to proptosis. The lacrimal gland may also become inflamed. Many patients with endocrine ophthalmopathy complain of a gritty foreign body sensation. Exposure keratoconjunctivitis, nocturnal lagophthalmos, lacrimal gland involvement, reduced amplitude of blinking (Pochin’s sign), and a reduced blink rate (Stellwag’s sign) all contribute to the symptoms of dry eye (Figure 12-10).

The exophthalmos of EO appears to be because of an increase in extraocular muscle volume displacing the

FIGURE 12-10 ■ Acute inflammatory endocrine ophthalmopathy with minimal exophthalmos and dramatic conjunctival chemosis and exposure keratopathy.

globe forward (Figure 12-11). The lid retraction (Dalrymple’s sign) and lid lag (von Graefe’s sign) result in a “thyroid stare” and are most likely the result of inflammatory adhesions between the levator aponeurosis and other fixed orbital tissues (Figure 12-12). The white bulbar conjunctiva above the upper limbus, usually hidden under the upper lid, is revealed. This condition is known a “baring of the sclera” (Figure 12-13).

An early sign of EO is periorbital swelling above the upper lids that is worse in the morning. This swelling may be caused by anterior displacement of orbital fat secondary to extraocular muscle enlargement or subcutaneous inflammation (Figure 12-14). Patients with

FIGURE 12-11 ■ Rapidly developing exophthalmos with marked chemosis.

FIGURE 12-12 ■ Severe bilateral upper lid retraction in endocrine ophthalmopathy.

FIGURE 12-13 ■ Extreme bilateral lid retraction. Note “baring of the sclera” with no signs of conjunctival chemosis.

FIGURE 12-14 ■ Note periorbital swelling of the upper and lower lids, with chemosis and exposure keratopathy.

more advanced EO may exhibit ocular motility restrictions (Ballet’s sign; Figure 12-15) with or without diplopia. This condition is invariably the result of enlargement and fibrosis of the extraocular muscles. The most common muscle involved in EO is the inferior rectus, which causes vertical diplopia increasing on upward gaze. A weakness of convergence may also be present (Moebius’ sign).

Visual acuity reduction in EO may occur secondary to corneal drying and induced astigmatism or from direct compression of the optic nerve by enlarged extraocular muscles. No inflammatory process appears to cause an optic neuritis, thus the optic neuropathy is the result of increased orbital volume. The greater the extraocular muscle volume, the more frequent is the optic neuropathy. Loss of color vision is also a result of this optic nerve compression. Visual field loss can occur in EO, but in no specific or predictable pattern.

Eye Signs. When diagnosing a patient with EO, the examiner should look for the following signs.

1. Extraocular muscle signs:

Ballet’s sign: a palsy of one or more extraocular muscles.

Möbius’ sign: a weakness of convergence. Suker’s sign: poor fixation on lateral gaze.

Wilder’s sign: jerking of eyes on horizontal versional movements.

2. Lid signs:

Boston’s sign: jerking of the upper lid as the patient looks down.

Dalrymple’s sign: lid retraction in primary gaze (elevation of upper lid margin above its normal resting level in primary gaze).

Enroth’s sign: edema of the lower lid.

Gifford’s sign: difficulty in everting the upper lid. Griffith’s sign: lower lid lag on upward gaze. Jellinek’s sign: increased pigmentation of lids

(Figure 12-16).

Joffroy’s sign: absence of forehead wrinkling on upward gaze.

Rosenbach’s sign: tremor of closed lids.

strated by sclera being exposed between the lateral canthus and lateral limbus in a fully abducted eye. This amount of exposed sclera is measured by a millimeter rule. The limitation of ductions is the best indicator of the severity of the disease.

5. Visual loss measurement. A loss of visual acuity should be assessed by visual acuity testing, slitlamp examination of the cornea, refraction and keratometry to rule out induced astigmatism, fluorescein dye testing, and Schirmer tear analysis. Tonometry readings should be taken in primary gaze and superior gaze.

If visual loss appears to be the result of optic neuropathy, then color vision testing using the FarnsworthMunsell l00-hue test or pseudoisochromatic plates is necessary. Automated, threshold, static visual fields are necessary to follow peripheral field losses in EO24 (Figures 12-17 and 12-18). Optic disc edema accompanied by an afferent pupillary defect may occur secondary to optic nerve compression.

Diagnostic Imaging Techniques

Ultrasonography. A-scan ultrasonography can measure the cross-sectional diameter of the extraocular muscle in question (Figure 12-19). B-scan ultrasonography produces a two-dimensional image of the muscle, and an experienced ultrasonographer is able to detect an enlarged diameter (Figure 12-20). Ultrasonography is performed without risk of radiation, in the office, and at a modest cost. It does require expertise and may miss muscle enlargement at the muscle apex.

Ossoinig has pointed out that standardized ophthalmic echography serves three functions in evaluat-

ing an EO patient: it diagnoses, confirms, or rules out EO; it follows the course and effectiveness of therapy; and it detects possible optic nerve compression. Echography confirms the presence of EO when three criteria are met: no mass lesion is detected, the orbital tissues are enlarged, and at least two extraocular muscles are thickened.

Computed Axial Tomography. High-resolution twodimensional images of the extraocular muscles, optic nerves, lacrimal glands, and orbits can be achieved with computed axial tomography (CT) scans. Specific characteristics of EO, such as extraocular muscle enlargement, proptosis, periorbital swelling, lacrimal gland swelling, and orbital apex crowding can be demonstrated with CT (Figures 12-21 and 12-22). The CT scan yields highly detailed anatomical studies and is commonplace, but the test uses radiation and continues to be expensive.

A CT scan of the orbits in a patient with severe EO can readily detect massive enlargement of the extraocular muscles with the thin muscle in sections. In addition, compression of the optic nerve by muscles at the orbital apex can be visualized. The location of the equator of the globe can be compared with that of the lateral orbital rim to document the exophthalmos (Figure 12-23). CT sections in two planes, the axial and coronal, should be ordered when evaluating a patient with EO. The coronal sections best reveal the enlargement of the extraocular muscles and measurements are possible (Figure 12-24).

Magnetic Resonance Imaging. Magnetic resonance imaging (MRI) improves on the CT scan by allowing for

FIGURE 12-19 ■ Transocular A scan with cross-section of thickened inferior rectus muscle in endocrine ophthalmopathy. (From Pickardt CR, Boergen KP, eds: Graves’ ophthalmopathy. Developments in diagnostic methods and therapeutical procedures. In Behrens-Baumann W, ed: Developments in Ophthalmology, vol 20, Magdeburg, Germany, 1989, Karger.)

even finer differentiation of soft tissue structure without requiring the use of ionizing radiation. MRI is not readily available, however, and is very expensive. Recently studies have shown that the T2-weighted image during MRI can accurately assess the acute inflammatory reaction within the orbital tissue. MRI sections in two planes, the axial and coronal, should be used in evaluating EO. The use of a paramagnetic contrast medium (gadolinium DTPA) has been advocated to help differentiate fi- brotic extraocular muscle changes from edema.

Laboratory Testing. The ELISA may reveal antibodies to eye muscle, but the test is not specific to EO and

FIGURE 12-20 ■ Top, patient with endocrine ophthalmopathy. Arrows pinpoint a dark region, which is a longitudinal section of muscle surrounded by fat (lighter zone). Notice the thinness of muscle insertions. Bottom, patient with myositis. Notice thickened muscle insertions. (From Wall JR, How J, eds: Graves’ ophthalmopathy, Boston, 1990, Blackwell Scientific.)

FIGURE 12-21 ■ CT scan image showing normal orbit. (From Pickardt CR, Boergen KP, eds: Graves’ ophthalmopathy. Developments in diagnostic methods and therapeutical procedures. In Behrens-Baumann W, ed: Developments in Ophthalmology, vol 20, Magdeburg, Germany, 1989, Karger.)

FIGURE 12-22 ■ CT scan image showing increased density of extraocular muscles in a patient with EO. (From Pickardt CR, Boergen KP, eds: Graves’ ophthalmopathy. Developments in diagnostic methods and therapeutical procedures. In Behrens-Baumann W, ed: Developments in Ophthalmology, vol 20, Magdeburg, Germany, 1989, Karger.)

FIGURE 12-23 ■ CT scan of patient with EO. Small arrows on the left denote massive enlargement of medial and lateral rectus muscles. Small arrows on the right show compression of the optic nerve. The large arrows point to the medial walls bowing inward secondary to increased pressure. Note that the equator (eq) is forward of the orbital rim (rim). (From Wall JR, How J, eds: Graves’ ophthalmopathy, Boston, 1990, Blackwell Scientific.)

FIGURE 12-24 ■ Coronal view of enlarged right inferior rectus (arrows). (From Pickardt CR, Boergen KP, eds: Graves’ ophthalmopathy. Developments in diagnostic methods and therapeutical procedures. In Behrens-Baumann W, ed: Developments in Ophthalmology, vol 20, Magdeburg, Germany, 1989, Karger.)

positive results occur in patients with other autoimmune disorders. In a patient with EO but no evidence of thyroid disease, detailed thyroid tests (TRH, T4, T3, and thyroid scan), thyroid antibody tests (including ELISA), and orbital scans help confirm the diagnosis. To confirm EO in a patient with hypothyroidism, ocular assessment includes exophthalmometry, measurement of lid signs, elevated intraocular pressure on superior gaze, and orbital scans.

Management (Box 12-5)

Amelioration of Risk Factor. Cigarette smoking has been shown to be a significant environmental risk factor in the development of EO. It has been postulated, but not proven, that cessation of smoking may prevent the onset of EO in genetically susceptible individuals.

Medical Management. Because of our poor understanding of the pathophysiology and evolution of EO and the lack of controlled clinical trials, managing this disorder remains difficult and controversial. The goals of medical management of EO are met if the EO is halted or reversed by antithyroid drugs and if the patient’s ocular signs and symptoms are largely controlled by various local therapeutic strategies, thus avoiding significant orbital complications. Some studies point to a beneficial effect on EO with use of antithyroid medications such as methimazole. No clear evidence exists yet, however, for the mitigation of EO with antithyroid medication.

Topical Therapy. Local measures to provide symptomatic relief of the ocular sequelae of EO, such as exposure keratopathy, provide significant relief for the patient but do not modify or ameliorate the disease process. These local maneuvers include the use of artificial tear solutions by day and lubricating ointment at night. The new viscous products (such as Celluvisc) provide good relief from asthenopia for many hours. If

142 CLINICAL MEDICINE IN OPTOMETRIC PRACTICE

BOX 12-5

THERAPEUTIC MANAGEMENT OF ENDOCRINE OPHTHALMOPATHY

Local symptomatic therapy

Artificial tear solutions

Artificial tear ointment

Nocturnal lid taping

Therapeutic and collagen contact lenses

Sleep with head elevated

Corrective prisms (for diplopia)

Medical management

Antithyroid drugs

Methimazole (Tapazole)

Propylthiouracil (PTU)

Potassium iodide

Beta-blockers

Immunomodulatory drugs

Systemic steroids

Cyclosporine

Methotrexate

Cyclophosphamide

Azathioprine

Plasmapheresis

Orbital radiation therapy

Orbital decompression

nocturnal lagophthalmos is present, taping the lids shut at night helps prevent exposure keratitis. Even dark sunglasses during the day help reduce the epiphora associated with EO. If exposure keratopathy worsens in spite of application of tear substitutes, the appropriate use of a therapeutic bandage soft contact lens may be helpful. A collagen corneal contact lens may be of value in particularly tenacious keratopathies. The patient who experiences periorbital edema that is worse in the morning should be advised to sleep with his head in a mildly elevated position.

Corrective prisms have limited use in patients complaining of diplopia secondary to EO. At best, the prisms allow for binocularity in only one particular position of gaze, because the restrictive nature of EO does not produce any consistent pattern of extraocular motility palsy. The prism correction may have to be repeatedly revised as the motility pattern changes over time. Stabilization of the diplopia may never occur, and this creates a frustrating experience for the patient.

Systemic Therapy. The goal of the medical treatment of EO is to slow or stop the inflammatory reaction in order to permit, if necessary, corrective eye surgery at an earlier stage. Medical therapy to ameliorate the actual disease process should be attempted when vision is threatened by corneal disease or optic neuropathy. Therapy consists of immunosuppressive agents given very early in the disease process when edema is causing extraocular muscle problems but no fibrosis has

occurred. The oral or intravenous use of large doses of glucocorticoids has been shown to reduce soft tissue edema. Many patients have responded favorably to ACTH and cortisone, and high-dose steroids are effective in 66% of patients.

Unfortunately, large doses of steroids produce the well-known side effects in most patients. Some investigators have pointed to the potential of retrobulbar injections of steroids to reduce potential systemic side effects, but the technique has found only limited use in the routine therapy of EO. Other studies point to cytotoxic and immunosuppressive drugs such as methotrexate, cyclophosphamide, and azathioprine (which inhibits T-cell proliferation) as possibly effective in the treatment of EO, but more research is needed.

The vast majority of the literature supports the finding that two of every three patients benefit from immunosuppressive therapy. The most favorable response to immunosuppression is a reduction in soft tissue signs, with moderate improvement in motility and vision loss. The least improvement is seen in the exophthalmos, which reduces on average by only 1 mm. Immunosuppressive therapy rarely cures the eye disease, and most patients need eye surgery, albeit at an earlier time, after immunosuppression.

Plasmapheresis. Plasmapheresis, or plasma exchange therapy, is a technique to extract antibodies from the blood, which, in autoimmune disorders such as EO, should theoretically be of benefit. A typical treatment plan has the patient undergo four plasmapheresis treatments in a 1-week period, followed by steroid (prednisolone) and azathioprine given for 3 months to reduce recurrences of EO. The amount of blood that is removed is replaced by solutions of plasma proteins. Clinical trials have shown that plasmapheresis is ineffective in chronic, nonprogressive EO but is very effective in early, acute, rapidly progressive EO. One third of the patients studied had recurrence of EO 6 months after cessation of immunosuppressive therapy. All patients were stabilized by another course of plasmapheresis and a shorter course of immunosuppressive agents.

Orbital Radiation. Radiation therapy makes use of well-collimated megavoltage irradiation generated by a linear accelerator and directed at retro-orbital structures, where there is a predominance of radiationsensitive lymphocytes in the infiltrate. Irradiation affects inflamed tissues in three ways. First, it corrects a state of acidosis by inducing ionization, thus converting the inflamed retrobulbar tissue to an alkylotic state. Second, lymphocytic activity is suppressed, thus mitigating this component of the inflammatory response. Third, fibroblasts are suppressed by radiation effects, with a consequent reduction of GAG production.

Orbital radiation therapy is well tolerated, with no long-term complications found in clinical studies (Figure 12-25). No cataract formation, radiation

FIGURE 12-25 ■ Stable fixation of head for orbital radiation therapy (European approach). (From Wall JR, How J, eds: Graves’ ophthalmopathy, Boston, 1990, Blackwell Scientific.)

retinopathy, or radiation-induced tumors have been reported in treated patients. Many patients have nearly complete resolution of signs and symptoms, and only one third of radiated subjects need to proceed to surgical treatment. Studies have shown that orbital radiation therapy in most cases halts progression of the disease, and in some cases improvement of signs and symptoms occurs. Orbital radiation therapy is recommended before surgical intervention to stabilize the ocular manifestations of EO. Like plasmapheresis, it is most effective in severe, progressive EO of recent onset.

Orbital Decompression. For almost a century surgical removal of one or more of the bones that compose the bony orbit has been performed for EO. This decompression procedure allows for expansion of the enlarged orbital contents and attempts to ameliorate many of the signs of dysthyroid orbitopathy, including proptosis. An otolaryngologist usually chooses the surgical procedure, and an ophthalmologist is present to assess the operation.

The surgical approach is usually tailored to the individual patient. For example, if the patient has posterior optic nerve compression because of an enlarged medial rectus muscle but little proptosis, the medial wall is removed all the way back to the sphenoid sinus. This allows the medial rectus to expand into the ethmoidal air sinus, thus reducing pressure on the optic nerve (Figures 12-26 and 12-27). If the medial rectus and inferior rectus are involved with mild proptosis, the medial wall and medial portion of the orbital floor are removed. With significant proptosis, threeor four-wall decompression with lateral wall or orbital roof removal can help reduce the exophthalmos.

Indications for orbital decompression include marked proptosis, corneal exposure with possible keratopathy, cosmetic disfigurement, or compression

FIGURE 12-26 ■ Compression of the optic nerve by enlarged medial rectus muscle, preoperative axial CT scan. (From Wall JR, How J, eds: Graves’ ophthalmopathy, Boston, 1990, Blackwell Scientific.)

FIGURE 12-27 ■ Postoperative view of orbital decompression showing deviation of medial rectus muscles medially into ethmoidal air spaces with relief of optic nerve compression. (From Wall JR, How J, eds: Graves’ ophthalmopathy, Boston, 1990, Blackwell Scientific.)

of the optic nerve that threatens vision. Other indications include orbital pain and orbital congestion resistant to steroids.

Before orbital decompression is attempted, the patient should have immunosuppressive therapy in an attempt to reduce the orbital disease. If steroid toxicity develops, radiation therapy is a valuable alternative. Only after these therapies have been tried and the ocular condition has been stabilized should orbital decompression be considered (Figure 12-28).

Orbital decompression may have serious complications. It has been noticed that in some cases the lid retraction actually worsens after surgery. In some cases the cornea may be abraded or the optic nerve injured (causing visual loss) during surgery. The most common complication of orbital decompression surgery is contraction of the rectus muscles, which causes postoperative diplopia. Only surgical recession improves this condition, and this should be attempted after swelling has subsided (approximately 3 months).

The expected results of orbital decompression surgery include improvement of visual acuity, resolution