Ординатура / Офтальмология / Английские материалы / Clinical Ocular Pharmacology 5th edition_Bartlett, Jaanus_2008

644 CHAPTER 32 Thyroid-Related Eye Disease

The most common cause of unilateral and bilateral proptosis in an adult is thyroid-related orbitopathy. This is not true for children in whom bilateral disease is usually from tumor and unilateral disease from infection. Although Graves’ disease and Hashimoto’s thyroiditis account for the largest proportion of patients with bilateral proptosis, the disorder can also be produced by neoplastic, vascular, and inflammatory processes and by infections, granulomatous processes, and other endocrine (Cushing’s and acromegaly) diseases. The term dysthyroid ophthalmopathy is used to include all forms of thyroid disease. Of course, pseudoproptosis (e.g., from a highly myopic globe), rectus paralysis, contralateral enophthalmos, asymmetric orbital size, or fissures must be excluded. Thus, the diagnosis of Graves’ ophthalmopathy can be made only by carefully excluding other possible causes of proptosis.

LABORATORY STUDIES FOR THYROID-RELATED ORBITOPATHY

The American Thyroid Association (ATA) issued updated guidelines for the use of laboratory tests in thyroid disorders. The emergence of highly sensitive thyrotropin (thyroid-stimulating hormone [TSH]) assays, capable of clearly separating normal from subnormal serum TSH levels, constitutes a practical and significant laboratory advance in clinical thyroidology. One should first measure the serum TSH level using a secondor third-generation immunometric assay with a sensitivity equal to or less than 0.01 mU/l, such as the TSH immunoradiometric assay or the sensitive TSH assay. This method of directly measuring the TSH levels permits a more rapid diagnosis of the thyroid status. Many of the older tests are less commonly used because of the advance of direct TSH evaluation. The free thyroxine (T4) used to measure unbound T4 in serum is not as reliable as the sensitive TSH. Likewise, the triiodothyronine (T3) resin uptake used to estimate T4-binding hormone capacity is relatively insensitive and inaccurate. Finally, the free T4 index, a mathematical calculation using T3 resin uptake and total T4 (tT4/T7) to estimate unbound T4 in serum, does not always correct for binding anomalies and is less sensitive than the sensitive TSH assay.

Once the TSH level is determined, the interpretation and additional testing are usually straightforward. Measurement of the TSH level is the only initial test necessary in a patient with a possible diagnosis of dysthyroid disease without evidence of pituitary disease. If patients have a normal TSH level, they are euthyroid. If their TSH level is elevated, they are hypothyroid. If the TSH level is low, implying hyperthyroidism, the tT4, which indicates total T4 (bound and free) in serum, is measured. The results are affected by binding anomalies;the tT4 may show false elevations in pregnancy, with oral contraception, with estrogen therapy, in hepatitis, and in those patients with a congenital excess of thyroid-binding globulin.

The tT4 may be falsely reduced with congenital deficiencies of thyroid-binding globulin, with testosterone or corticosteroid therapy, with drugs that bind to thyroidbinding globulin, or in those who are severely ill. If the tT4 is normal and the TSH is low, the total T3 (tT3) test may be analyzed for issues of thyroid-binding globulin binding problems or patients with thyrotoxicosis. The tT3 test measures tT3 in serum and is less subject than tT4 to binding abnormalities. It is more useful after the diagnosis of hyperthyroidism.

The radioactive iodine (RAI) uptake and thyroid scan are nonroutine tests. The RAI uptake test is used to diagnose the cause of hyperthyroidism and is particularly useful in calculating the dose when iodine is used in treatment. Radionucleotide uptake and scan easily distinguish the high uptake of Graves’ disease from the low uptake of thyroiditis. A thyroid scan is useful in identifying those areas of the thyroid in which thyroid function is altered from singular or multiple nodules of the gland. Malignancy should be considered in cases with active or multiple nodules.Thyroid autoantibody measurements are specialized tests used to identify immunologic forms of thyroid disease. A complete discussion of thyroid autoantibodies is beyond the scope of this text.

EPIDEMIOLOGY OF THYROID-RELATED ORBITOPATHY

In 1960 three phases found in thyroid-related orbitopathy were described: the initial dynamic phase, a static phase, and a final quiescent phase. The dynamic phase results in eyelid retraction and proptosis. The static phase shows little improvement. The quiescent phase can show some improvement in eyelid retraction and ocular motility.

There are two basic categories of thyroid-related orbitopathy: infiltrative and noninfiltrative. Approximately 90% of patients have noninfiltrative disease. Noninfiltrative (class 1) thyroid-related eye disease is characterized by the mildest form of ocular involvement, with eyelid retraction but minimal proptosis. This occurs in up to 50% of patients with toxic diffuse goiter and can begin at any age, but patients tend to be younger, and female persons outnumber male persons in a ratio of up to 6:1.

Recent data suggest that thyroid orbitopathy is a disease most common in younger women but more severe, by most indices, in men and patients older than 50 years.These latter patients are also more likely to have asymmetric or euthyroid manifestations of the disease.

Smoking is a risk factor for Graves’ hyperthyroidism and worsening orbitopathy in women. The relationship was also dose dependent. Those with the highest risk of Graves’ hyperthyroidism were women with the greatest number of pack years of smoking and current smokers who smoked the most cigarettes per day. The mechanism by which smoking increases the risk of Graves’orbitopathy remains unknown.

Graves’ ophthalmopathy develops in more than 80% of cases within 6 months of the diagnosis of Graves’ hyperthyroidism. Graves’ ophthalmopathy may occasionally develop before the diagnosis of hyperthyroidism. Thyroidrelated orbitopathy is associated with Graves’ hyperthyroidism in 90% of cases and with autoimmune thyroiditis (Hashimoto’s disease) in some 5%. No laboratory evidence of thyroid disease is found in 5% to 10% of patients. This condition is called ophthalmic or euthyroid Graves’ ophthalmopathy.

ETIOLOGY OF THYROID-RELATED ORBITOPATHY

Although the precise etiology of Graves’ ophthalmopathy is not well understood, a basic knowledge of the pathology associated with the disease is essential for an understanding of the mechanisms of action of the various drugs and other therapeutic modalities used in managing this disorder. The ocular involvement associated with dysthyroid state is primarily an orbital disease, and pressure–volume relations within the orbit are critical in the pathogenesis of Graves’ ophthalmopathy.The most striking pathologic feature of thyroid-related orbitopathy is the marked enlargement of the extraocular muscles.

This enlargement is accompanied by mononuclear cell infiltration and proliferation of orbital fibroblasts. These cells release cytokines coincident with increased production of collagen and glycosaminoglycans into the interstitial space of extraocular muscle fibers, orbital fat, and orbital connective tissue. The activated T cells, directed against thyroid follicular cell antigens, are thought to interact with the orbital fibroblasts. The result is an increase in edema of these tissues and degenerative changes within the muscle cells. The current view is that thyroid-related orbitopathy is a T-cell–mediated autoimmune disease. Activated T cells releasing the cytokines interleukin-1α, interferon-γ, and tumor necrosis factor-β stimulate retroorbital fibroblast glycosaminoglycan production, with attendant edema, swelling of the muscles, and an increase in retroorbital tissue. These inflammatory changes result in the clinical manifestations of ophthalmopathy; proptosis, and many of the other signs of Graves’ ophthalmopathy. It was hypothesized that almost all the secondary effects of thyroid-related orbital infiltration are circulatory and that the visual field loss and color vision dysfunction are typical of optic nerve involvement either by direct compression or by interference with vascular circulation.

The role of the immune system in the pathophysiology of Graves’ disease is well established. A considerable amount of information links the human major histocompatibility complex (human leukocyte antigen [HLA]) with Graves’ disease. For instance, several HLA types, such as HLA-B8 and HLA-DR3, are associated with this disorder. Graves’ disease in the Japanese has been found to be associated with HLA-B35, whereas in patients of Chinese

origin HLA-Bw46 confers a greater risk. Risk ratios indicating an increased probability for patients to develop Graves’ hyperthyroidism range from threeto fivefold, which suggests a relatively weak association. No specific gene has been found to date.

Thyroid orbitopathy is an inflammatory disease of the orbital tissues. This inflammation is mediated through cytokine release, proliferation of fibroblasts, increased deposition of extracellular matrix, and adipocyte differentiation and proliferation. These cellular changes result in enlargement of the extraocular muscles and increased volume of orbital soft tissues, which presents clinically as exophthalmos and optic nerve compression. Edema, inflammation, and late fibrosis account for the decreased function of the extraocular muscles despite relative preservation of the muscle fibers themselves.

CLASSIFICATION OF GRAVES’

OPHTHALMOPATHY

The clinical presentation of Graves’ orbitopathy can be subdivided into predominantly “congestive” orbitopathy and “inflammatory” orbital myopathy. Predominantly congestive orbitopathy (type I) accounts for approximately 30% of all cases. It is characterized by inflammatory infiltration of the orbital connective tissues and orbital fat with relative sparing of the extraocular muscles. The infiltration, which causes inflammation, is often associated with edema and may, if severe, progress to fibrosis. These patients have less diplopia and pain with milder proptosis. The inflammatory orbital myopathy (type II) presents in about 10% of patients with inflammation, swelling, and dysfunction of the extraocular muscles complaining of painless diplopia.The inflammatory form appears to attack the extraocular muscles as the primary target. The process is characterized by white blood cell infiltration of orbital fibroadipose and skeletal muscle tissue. These patients experience diplopia, orbital pain, and proptosis and may require surgical intervention. A combination of these two subtypes is found in the remainder of the patients.

There are two main grading systems used today for Graves’ orbitopathy: NOSPECS, developed and used by most endocrinologists, and the Clinical Activity Score, which places greater emphasis on inflammatory changes found in Graves’ orbitopathy. For simplicity, we discuss and use the NOSPECS grading system for Graves’ orbitopathy.

To achieve uniformity in terminology regarding the various ocular changes associated with thyroid disease, in 1968 the ATA adopted an initial classification of the ocular changes of Graves’ disease. Various modifications to the original classification system have been proposed, and one by an endocrinologist has been approved by the ATA (Tables 32-1 and 32-2). Each class usually (but not necessarily) includes the changes indicated in the preceding class. This classification, however, suffers from

646 CHAPTER 32 Thyroid-Related Eye Disease

Table 32-1

Abridged Classification of the Eye Signs in

Graves’ Disease

Class Definition (mnemonic “NOSPECS”)

0No physical signs or symptoms

1Only signs, no symptoms (e.g., upper eyelid retraction, stare, and eyelid lag)

2Soft tissue involvement (symptoms and signs)

3Proptosis

4Extraocular muscle involvement

5Corneal involvement

6Sight loss (optic nerve compression)

Reprinted with permission from Werner SC. Modification of the classification of the eye changes of Graves’ disease. Am J Ophthalmol 1977;83:725–727; and ETA, LATS, JapaneseAOTA, ATA. Classification of eye changes of Graves’ disease. Thyroid 1992;2:235–236.

several flaws. There is a lack of natural progression from one class to the next. Also, the classification fails to distinguish between the active and inactive forms of the disease. Finally, there seems to be a poor relationship between the class designation and the severity of the ophthalmopathy. The first letters of each definition form the mnemonic NOSPECS, with NO indicating the usually nonthreatening prognosis of classes 0 and 1 and SPECS indicating the relatively serious nature of classes 2 through 6.

The ATA and the European, Latin-American, and Japanese and Asia-Oceania thyroid associations reexamined the content and applications of the NOSPECS classification, reaching consensus on the following points. First, the NOSPECS classification is an ingenious memory aid for clinical examination of the orbital changes of Graves’ disease, has useful educational application, and is descriptive of the ocular changes that occur in the disease process. Second, the classification and its numeric indices are less satisfactory for objective assessment of the orbital changes of Graves’ disease and for reporting results of clinical studies. Regarding the evaluation of treatment response, specific and separate measurements relating to the status of eyelids, cornea, extraocular muscles, proptosis, and optic nerve function should be recorded.

An assessment of inflammatory activity of Graves’ ophthalmopathy is relevant to therapy. Disease activity at any one time may be assessed by assigning one point to each of the following signs and symptoms: spontaneous retrobulbar pain,pain on eye movement,eyelid erythema, conjunctival injection, chemosis, swelling of the caruncle, and eyelid edema or fullness. The sum of these points defines the clinical activity score (range, 0 to 7). The clinician should realize that activity scores are untested and subjective. Finally, an important element in evaluating the effects of treatment of Graves’ ophthalmopathy is the patient’s self-assessment. Such assessments, described on

Table 32-2

Detailed Classification of the Eye Changes of Graves’

Disease

a3- to 4-mm increase over upper normal

b5- to 7-mm increase

c8-mm or greater increase

aLimitation of motion at extremes of gaze

bEvident restriction of motion

cFixation of globe (unilateral or bilateral)

bSame; acuity 6/22 (20/70)–6/60 (20/200)

cBlindness (failure to perceive light),

acuity less than 6/60 (20/200)

Reprinted with permission from Werner SC. Modification of the classification of the eye changes of Graves’ disease. Am J Ophthalmol 1977;83:725–727.

scales of best to worst, should include appearance, visual acuity, eye discomfort, and diplopia.

Class 1 Disease

Class 1 disease, formerly termed mild or noninfiltrative disease, is characterized by upper eyelid retraction (Figure 32-1) and occurs in more than 90% of patients with hyperthyroidism. This sign may initially occur unilaterally or bilaterally and is often asymmetric. A helpful diagnostic sign often associated with eyelid retraction is the lid tug sign, in which the retracted upper lid offers a sensation of increased resistance on attempted manual lid

Figure 32-1 Upper eyelid retraction characteristic of class 1 Graves’ ophthalmopathy.

closure (Grove’s sign). The resistance to eyelid closure is noted by simply grasping the lashes of the upper lid and gently pulling down. The amount of resistance is compared with the contralateral lid in unilateral cases or with a control normal eyelid in cases of bilateral lid retraction. This test is particularly helpful in cases of questionable bilateral retraction or ambiguous unilateral retraction versus contralateral ptosis.

Eyelid retraction can produce findings in several associated tests that may correlate with the onset of the ophthalmopathy. Marginal reflex distance can be used to assess upper eyelid retraction. A light source is placed in front of a patient in primary gaze to produce a corneal reflex. This distance between the corneal reflex and the upper eyelid margin is measured. The normal measurement is 4 to 5 mm. Another possible finding is a reduction in the tear breakup time of one or both eyes. Eyelid retraction causes an increase in the ocular surface area that must be covered by the tear film, and there is an associated decrease in blink frequency in Graves’ patients. An increase in tear osmolarity also affects the mechanics of tear stability in these patients. The combination of these factors affects stability of the tear film.

The most common cause of eyelid retraction is hyperthyroidism. Although eyelid retraction most frequently is associated with Graves’ ophthalmopathy, other diseases may cause this sign, especially if normal thyroid function and regulation are confirmed. There are four major hypotheses for the pathogenesis of thyroid-associated lid retraction. First, in the early stages there is excessive stimulation of Müller’s muscle in the upper eyelid associated with sympathetic stimulation and increased levels of thyroid hormone resulting from the marked inhibition of liver monoamine oxidase synthesis by high circulating T4 levels. Second, in long-standing Graves’ disease the inferior rectus muscle becomes fibrotic. The superior rectus–levator muscle complex must overcontract on attempted up-gaze to counteract the fibrotic inferior rectus muscle. Third, there is mechanical restriction of the levator muscle, with increased orbital volume that

causes anterior displacement of the globe, resulting in further eyelid retraction.

There is negligible lymphocytic infiltration, and the extracellular volume is not increased in the levator muscle. However, the muscle fibers become greatly enlarged, leading to hypertrophy of the levator muscle and upper eyelid retraction.

Lid retraction can appear in the presence of chemical and clinical euthyroidism and is often unrelated to control of any existing thyroid dysfunction. Eyelid lag (von Graefe’s sign) often accompanies lid retraction (Figure 32-2), but lid lag by itself is not pathognomonic of thyroid eye disease. Lid retraction disappears spontaneously after 15 years in approximately 60% of patients.

Class 2 Disease

Classes 2 through 6 of the disease,congestive orbital disease, represent the more significant and vision-threatening changes associated with Graves’ disease. Some important clinical signs of class 2 disease are swelling of the eyelids; prolapse of orbital fat,nasally in the upper lid and temporally

A

B

Figure 32-2 Eyelid lag (von Graefe’s sign). After extreme up-gaze (A), the upper eyelids remain retracted and fail to assume their normal depressed position on down-gaze (B).

648 CHAPTER 32 Thyroid-Related Eye Disease

Figure 32-3 Class 2 Graves’ ophthalmopathy with upper and lower eyelid swelling, injection of conjunctival and episcleral vessels, and chemosis.

in the lower lid; a palpable lacrimal gland; injection of the conjunctival and episcleral vessels; and chemosis (Figure 32-3). These changes result in symptoms of lacrimation, light sensitivity, and gritty or sandy foreign body sensation. Orbital inflammation and edema during sleep may make these symptoms worse in the morning upon awakening. Contact lens patients may complain of sudden intolerance to lens wear. Graves’ patients usually develop systemic symptomatology before or simultaneously with observable ocular signs. Inflammation and hypertrophy of the extraocular muscles (Figure 32-4) are common and are of diagnostic value in those patients even without observable proptosis.

Class 3 Disease

The incidence of proptosis in patients with hyperthyroidism is high, with estimates ranging from 40% to 75%. Class 3 Graves’ ophthalmopathy is defined as at least

Figure 32-4 Inflammation and early hypertrophy (arrows) of the insertion of the lateral rectus muscle in a patient with class 2 Graves’ ophthalmopathy. White spots in center are photographic artifacts.

23 mm of proptosis. The proptosis is almost never an isolated finding and is commonly associated with soft tissue findings and extraocular muscle involvement. If proptosis is the only presenting complaint, other etiologies of orbital disease should be investigated. Two-thirds of patients with Graves’ ophthalmopathy develop exophthalmometry readings of 23 mm or more. Although computed tomography (CT) and ultrasonography (US) evaluations reveal extraocular muscle involvement, the degree of proptosis does not necessarily parallel the severity of the orbital inflammatory process. One mechanism for proptosis associated with thyroid orbitopathy has been partially clarified. Increased orbital deposition of glycosaminoglycans (mucopolysaccharides) occurs as the result of both hormonal and immunologic mediators. Approximately 50% of thyroid patients have an increase in orbital fat, and of these patients 10% show this increase as the only sign on CT or magnetic resonance imaging (MRI) examination. The proptosis may give rise to secondary lagophthalmos (Figure 32-5). Additionally, ocular hypertension in patients with Graves’ ophthalmopathy is caused,in part,by increased intraorbital pressure associated with proptosis.

Like eyelid retraction,proptosis can begin unilaterally and should therefore be differentiated from the apparent proptosis simulated by unilateral lid retraction. This distinction can often be accomplished clinically by measurement using the Luedde or Hertel exophthalmometer, with which the upper limits of normal are approximately 18 mm for Asians, 20 mm for whites, and 23 mm for blacks (Table 32-3).A 2-mm or greater difference between eyes should be considered abnormal and justification for further study. Another helpful test is palpable retropulsion. With patients’ eyes closed, digital palpation of the globes results in less detectable resistance in thyroid orbital disease as opposed to a greater resistance from an orbital tumor. Because hyperthyroidism is the most common cause of unilateral proptosis, the investigation of unilateral proptosis in patients without other signs of Graves’ ophthalmopathy should include serum TSH levels. The degree of proptosis does not correlate well with compressive optic neuropathy. One might encounter compressive optic neuropathy with very mild proptosis in patients with shallow orbits.

Class 4 Disease

Approximately 14% of patients with thyrotoxicosis and 33% of patients with Graves’ ophthalmopathy develop class 4 involvement, in which the inflammatory changes result in loss of elasticity and fibrosis of the extraocular muscles. The usual diplopic pattern in symptomatic patients is hypertropia with or without esotropia. The esotropia is due to involvement of the medial rectus muscle. Exotropia is so uncommon in Graves’ orbitopathy that one should suspect myasthenia gravis as a possible etiology in acquired exotropia. Myasthenia gravis has

no set pattern of extraocular muscle involvement. It can mimic any ocular motor cranial nerve palsy or central gaze disturbance. Thyroid eye disease usually starts with an “elevator palsy” due to inferior rectus involvement followed by a set pattern of recti muscle involvement with the lateral recti muscle being much less involved. More than 90% of Graves’ patients have US and/or CT evidence of extraocular muscle involvement. Most commonly, patients with class 4 disease are women between the ages of 40 and 60. Characteristically, on US or CT the muscle belly is enlarged, but the disease process spares the tendinous portion near the insertion, allowing differentiation from myositis.

Electromyography and saccadic velocity studies demonstrated that the mechanical restriction of the eye is caused by interstitial edema and fibrosis of the muscles rather than by myopathy. However, in the acute phases of Graves’ orbitopathy saccadic velocity testing demonstrates a neuropathic state, which resolves on fibrosis.

Table 32-3

Exophthalmometry Values in Healthy Adults

The most common muscle to be involved is the inferior rectus, which is affected in 60% to 70% of cases (Figure 32-6). Twenty-five percent of patients have a fibrotic medial rectus muscle, and only 10% or fewer demonstrate a fibrotic superior rectus muscle. CT, MRI, and US demonstrate more generalized extraocular muscle enlargement than can be appreciated clinically, yet examination generally reveals greater inferior and medial recti involvement. Differentiating a fibrotic muscle from paresis of its antagonist is essential and can be achieved by performing a forced duction test, as described in Chapter 19. It is unclear why oblique muscle involvement in the disease process is rare.

Because the inferior rectus muscle usually undergoes fibrosis early, attempted up-gaze exerts traction on the globe, which elevates the intraocular pressure (Braley’s sign).This phenomenon occurs in approximately 20% of patients with Graves’ disease and indicates fibrosis of the inferior rectus muscle; more importantly, the absence of glaucoma can be confirmed on visual field testing, performed to rule out optic nerve compression.

Class 5 Disease

Adapted from Migliori ME, Gladstone GJ. Determination of the normal range of exophthalmometric values for black and white adults. Am J Ophthalmol 1984;98:438–442.

Class 5 involvement poses a significant threat to visual function because of exposure keratopathy secondary to lagophthalmos and proptosis (Figure 32-7). Corneal exposure may be particularly severe if there is significant upper eyelid retraction, proptosis, and an abolished Bell’s reflex associated with fibrosis of the inferior rectus muscle and limitation of up-gaze. Most patients with proptosis greater than 23 mm show staining of the inferior cornea on careful biomicroscopic examination. Staining of the central cornea should alert the examiner to potential exposure keratitis. Unless the disorder is

650 CHAPTER 32 Thyroid-Related Eye Disease

A

B

Figure 32-6 (A) Note the asymmetry of visible sclera above each lower eyelid (arrows). By prism measurement this patient has an 8D left hypotropia in primary gaze.

(B) Restriction of the left inferior rectus muscle on gazing up and left.

managed aggressively secondary corneal ulceration can ensue, with the potential risk of endophthalmitis.

Superior limbic keratoconjunctivitis is associated with thyroid dysfunction and appears to be a prognostic marker for severe Graves’ ophthalmopathy. Approximately onehalf of patients with superior limbic keratoconjunctivitis have eyelid retraction and one-half have eyelid lag. Whether eyelid retraction is causative or merely associated is unclear. Several patients exhibited resolution of the superior limbic keratoconjunctivitis after eyelid retraction surgery or orbital decompression.

Figure 32-7 Severe exposure keratopathy of the left eye of a patient with class 5 Graves’ ophthalmopathy.

Class 6 Disease

The incidence of optic neuropathy in thyroid eye disease is 5% to 10%. The class 6 patient usually has mild to moderate proptosis and relatively shallow orbits. Thyroid optic neuropathy may be evidenced by papilledema, papillitis, or retrobulbar neuritis and usually is characterized by a painless and gradual loss of visual acuity. Common visual field defects include central scotomas, arcuate or altitudinal defects, paracentral scotomas, or generalized depressions. Thus visual field and optic disc examinations are the best diagnostic tools for early optic neuropathy. Occasionally, vision loss can occur precipitously over 1 or 2 weeks. Other features of optic nerve dysfunction frequently associated with the decreased visual acuity are color vision disturbances, afferent pupillary defects in the less proptotic eye in patients with asymmetric involvement, and prolongation of the pupil cycle time.

Recent CT and MRI studies showed that increased extraocular muscle volume correlates with compressive optic neuropathy as well. Although some patients show inflammation of the nerve and sheath, it has been postulated that these patients have shallow orbits or that they lack the ability to decompress anteriorly. Patients at greater risk of developing optic neuropathy are older patients with enlarged extraocular muscles and limited motility. Diabetic patients with proptosis and extraocular muscle enlargement are also more likely to develop optic neuropathy.

DIAGNOSTIC IMAGING OF THE ORBIT

High-resolution orbital imaging using high-resolution CT, MRI, and US has significantly simplified the differential diagnosis of proptosis by eliminating such causes as orbital tumors or idiopathic myositis and often establishing the bilateral nature of the disease. High-resolution CT and MRI are now used in most centers. Both techniques work well in the critical area of the orbital apex, where US is less applicable. An advantage of MRI over CT is that MRI demonstrates tissue differentiation better than does CT. However, MRI requires a longer examination time and is somewhat more expensive.

Orbital US examination, CT, and MRI are the most helpful noninvasive techniques for the diagnosis of Graves’ ophthalmopathy. Advances in US and high-resolution CT with supplemental multiplanar computer-generated reformations have significantly increased the ability to predict the location of most orbital pathology. Pulse sequences that examine T2-weighted MR images can estimate water content of orbital tissues. When examining the extraocular muscles, normal T2 images might imply burned out fibrotic disease with low water content, whereas prolonged T2 images might suggest ongoing inflammation with tissue edema possibly amenable to immunosuppressive medications or orbital radiation. These procedures are particularly valuable when the

patient is clinically and chemically euthyroid, because they may demonstrate evidence of enlarged extraocular muscles before clinical signs and symptoms arise.

CT and MRI confirm the diagnosis of Graves’ ophthalmopathy in euthyroid patients and in those with atypical or severe clinical manifestations, including compressive optic neuropathy. The extraocular muscle enlargement is seen to occupy the nontendinous (belly) portion of the muscles (Figure 32-8). Advantages of MRI over CT include higher spatial resolution, absence of bone artifacts, direct multiplanar imaging, and increased tissue contrast. However, consideration must be given to the fact that CT is often more readily available than MRI.

Orbital US, CT, and MRI are commonly used as imaging techniques to demonstrate pathologic changes in the orbital tissue in Graves’ patients. Low cost, short time investigation, and lack of radiation characterize orbital US, a technique that should be given consideration by the health provider.When orbital disease activity or exclusion of orbital pathology is required, CT or MRI is particularly useful for these diagnostic purposes.Additionally, sudden visual acuity or field loss in a known thyroid patient requires CT or MRI to demonstrate possible optic nerve compression at the apex of the orbit.

OctreoScan has the unique ability to detect octreotide, a somatostatin analogue labeled with indium. This scan

technique has been used to localize tumors that possess membrane receptors for somatostatin in vivo and predict the inhibitory effect of octreotide on hormone secretion by these tumors. OctreoScan has been used to detect accumulation of the radionucleotide in both the thyroid gland and orbits of patients with Graves’ disease.

CLINICAL COURSE OF GRAVES’

OPHTHALMOPATHY

The orbitopathy has both an active and quiescent stage. The active stage lasts between 6 and 24 months and includes a wide spectrum of orbitopathy changes and patient symptomatology. The quiescent stage may include patient improvement in both orbitopathy and symptomatology and can last for many years. The clinical manifestations of ophthalmopathy do not correlate with the thyroid disease course or activity. The ocular changes may appear before, during, or after the onset of thyrotoxicosis but usually occur within 18 months before or after the diagnosis of hyperthyroidism. It was asserted that ocular involvement, even if subclinical, is an inevitable complication of Graves’ disease. All classes of ocular changes occur in euthyroid Graves’ disease as well as in the euthyroid phase of hyperthyroidism. The course and duration of changes in classes 2 through 6 are extremely unpredictable,

652 CHAPTER 32 Thyroid-Related Eye Disease

with progression from class 1 to class 6 often being irregular. Progression from class 1 through class 6 occurs in approximately 5% of patients, even after subtotal thyroidectomy or RAI therapy. The onset is usually subacute, with one eye frequently being affected before its fellow. The natural history of the ocular disease from onset to spontaneous remission usually covers 6 months to 3 years (mean, 2 years), after which the patient usually manifests a residual eyelid retraction,lid fullness,proptosis, and fibrotic changes of the extraocular muscles. Because of the tendency for Graves’ ophthalmopathy to undergo spontaneous remission, medical or surgical treatment is intended to prevent permanent ocular damage rather than to arrest or retard progression of the disease process.

MANAGEMENT OF GRAVES’

OPHTHALMOPATHY

Because the natural history of Graves’ ophthalmopathy is to undergo spontaneous remission, evaluating the effectiveness of various forms of treatment is sometimes difficult. Also, one must know the phase in which the patient is identified because this, too, affects the treatment. With the knowledge that some eyes are lost solely due to failure to provide treatment, appropriate therapeutic measures may serve to reduce the risk to visual function and provide the patient with symptomatic relief.

The management of noninfiltrative disease should be conservative. This approach should include patient education, reassurance, and treatment of any underlying thyroid abnormality and regular follow-up to provide treatment for dry eye. The disorder may not be truly quiescent for 2 to 3 years. After this point, if the symptoms are stable, surgical intervention for residual diplopia or other orbital changes may be considered.

The management of infiltrative disease should be appropriately aggressive. The presence of active class 2 through class 6 disease calls for prompt treatment as soon as the diagnosis is confirmed. Because the clinical manifestations of class 2 through class 6 disease are mostly caused by loss of critical orbital volume, therapy should be directed to rapidly restoring those relations toward normal. These patients are more likely to develop compressive optic neuropathy. They also tend to be older and have subsequent motility disorders. Patients with infiltrative disease and proptosis are less at risk, and they frequently do not require surgical decompression, because the proptosis is a decompressing event.However,those patients with infiltrative disease and no proptosis are most likely to need urgent irradiation and anti-inflammatory therapy. This represents a major difference between Graves’ orbitopathy and other causes of proptosis.

Regardless of the stage of ocular involvement, certain general principles of management apply. Because most patients with Graves’ ophthalmopathy go through a period of initial worsening followed by a plateau of variable length and, finally, spontaneous improvement,

patients should be monitored more closely if they are in the worsening phase. If spontaneous improvement is occurring, more vigorous forms of treatment, such as surgery or high-dose steroids, should be withheld.

Many patients, if relieved of the fear of losing vision, are willing to accept surprising degrees of cosmetic change and sometimes demanding treatment modalities. Several studies showed that patients with severe eye signs smoked significantly more tobacco than did those with less serious signs. Advising the patient that smoking cessation might have a positive impact on both the hyperthyroid status and the orbitopathy is very important in the treatment of the disease.

The patient should be advised of the marked variations in the course of the ocular disease and its relatively imprecise association with the status of the thyroid gland. This information may reassure the patient and maintain rapport between the practitioner and patient if the condition worsens in its later stages.

A major problem in devising effective treatment has been an inadequate understanding of the factors that cause the ocular disease. Despite this lack of knowledge, management of Graves’ ophthalmopathy involves treating the thyroid dysfunction, relieving ocular pain and discomfort, restoring and protecting vision, and improving cosmetic appearance. The following recommendations are representative of the most effective treatment modalities currently available.

Management of Thyrotoxicosis

As part of the treatment of Graves’ ophthalmopathy, adequate control of the dysthyroid state, if it exists, is essential. The antithyroid drugs propylthiouracil (PTU) and methimazole (MMI), 131I, and thyroidectomy are the three major modalities used in the treatment of hyperthyroidism. In addition, β-adrenergic blocking agents, such as propranolol, are useful for the rapid control of sympathetic nervous system manifestations. Nonselective betablockers such as propranolol are preferred because they have a more direct effect on hypermetabolism. There is general agreement that the hyperthyroid state and the ocular disease may run independent courses. Although control of hypermetabolism is necessary, this control does not ensure that the ophthalmopathy will improve concomitantly with treatment of the thyroid imbalance. However, it is essential in the treatment of the thyrotoxicosis to bring the patient gradually to euthyroidism by avoiding abrupt and exaggerated changes in the thyroid state. The ocular changes may be more likely to progress after systemic treatment that causes rapid alteration in thyroid function. Consultation with an endocrinologist is considered standard of care.

Results of survey studies among thyroid specialists who treat Graves’ hyperthyroidism in Europe, Japan, or the United States showed consensus only on the relative lack of a role of thyroidectomy, except for narrow indications.

Graves’ hyperthyroidism in the United States is treated in most adults (69%) with 131I, whereas the remaining patients receive treatment with the antithyroid drugs PTU or MMI. Conversely, antithyroid drugs are used in Europe (77%) and Japan (88%) in most Graves’ disease patients, whereas the rest are treated with RAI.

Most patients with Graves’ disease respond adequately to an initial dose of PTU, 300 to 450 mg, or MMI, 30 to 45 mg/day in divided doses. Doses should be adjusted subsequently by clinical response and thyroid hormone determinations. Several management options exist once the patient’s hyperthyroidism has been controlled with antithyroid drugs. Some physicians reduce the dose of medication, whereas others, to maintain a euthyroid state, provide thyroid hormone replacement without modifying the amount of antithyroid drug. The use of antithyroid drugs may diminish the serum hormone level, requiring thyroid hormone replacement or discontinuation of the drug. RAI treatment is generally reserved for patients older than 30 years.

In the United States 131I remains the mainstay of initial therapy of thyrotoxicosis. Most patients with Graves’ disease respond adequately to doses of 131I of between 5 and 10 mCi.

Rarely,subtotal thyroidectomy is elected in certain cases but should not be performed until the patient’s disease is under adequate control. Surgery is usually preferred for pregnant women whose thyrotoxicosis is not controlled with low doses of thioureas, for patients with particularly large goiters, and whenever there is a significant chance of malignancy. Patients developing hypothyroidism should receive L-T4, 0.1 to 0.2 mg/day (1.6 mcg/kg body weight/day). These patients should be monitored at regular intervals by serum TSH determinations.

The frequency and types of toxic reactions to PTU and MMI are similar but appear to be related to the doses used. Methimazole usually is the drug of choice in nonpregnant patients because of its lower cost, longer half-life, and lower incidence of hematologic effects. Conversely, PTU is preferred for pregnant women because MMI has been associated with rare congenital anomalies. Approximately 5% of patients experience mild side effects, ranging from gastrointestinal complaints to mild skin reactions and pruritus, which can usually be controlled adequately with antihistamines without discontinuing the antithyroid drug. The most severe and worrisome complication, however, is agranulocytosis, which occurs in approximately 0.1% to 0.5% of patients treated with these drugs. It always responds to discontinuation of the medication, but in a few instances concomitant administration of steroids may be indicated. Because this complication can be lethal if not quickly recognized, the patient should be advised to report to the physician whenever infection, sore throat, or general malaise occurs, in which case a complete blood count should be obtained.

In 15% of patients Graves’ orbitopathy can develop or be worsened by the use of radioactive iodide.

The concomitant use of oral prednisone (40 to 80 mg) tapered over at least 3 months can prevent or improve severe eye disease in two-thirds of patients. Lower dose RAI sometimes is used in patients with the orbitopathy because of posttreatment hypothyroidism, which also may be associated with exacerbation of the eye disease.

Local Management of Ophthalmopathy

A variety of local measures can be used to provide the patient with symptomatic relief while protecting ocular tissues and preserving visual functions. Certain measures apply to each disease classification.

Class 1 Disease (Eyelid Retraction)

The patient with class 1 disease may have lagophthalmos ranging from very mild to very severe.The eyelid retraction and lagophthalmos accelerate tear film evaporation, thus increasing tear film osmolarity and causing ocular surface damage. Any associated exposure keratopathy should be managed with ocular lubricating solutions or ointments. The clinician should try several types of nonpreserved artificial tears. This trial method allows the patient to choose the artificial tear formulation that gives the greatest symptomatic relief. Topical nonsteroidal antiinflammatory drugs such as 0.5% ketorolac (Acular) in the preservative-free form or 0.1% diclofenac (Voltaren) may be used to reduce ocular irritation. Punctal occlusion therapy has met with limited success in these patients. Additionally, the use of topical cyclosporine (Restasis) may also provide dry eye relief,but because of the variability in severity of exposure keratopathy the use of topical cyclosporine should be considered on a case-by-case basis.

A variety of general measures may be helpful, such as the wearing of tinted lenses to shield the undesirable cosmetic appearance and to protect the eye from wind, dust, and other environmental factors. Bandage soft contact lenses may be used to reduce ocular irritation from exposure and may provide temporary relief during the day. The eyelids can be taped shut at bedtime to protect the cornea. Likewise, a plastic-wrap shield can be constructed and taped over the eye, thus creating a moisture chamber during sleep. Moreover, certain sleep positions may increase the effects of the lagophthalmos. Many clinicians have observed patients who sleep in the prone position to have more ocular symptoms than do those who sleep supine. Elevation of the head of the bed helps to reduce overnight swelling and congestion. For moderate to severe cases of corneal exposure, applying a topical broad-spectrum antibacterial ointment (e.g., bacitracin– polymyxin B) at bedtime or continuously during the day may prevent infection of the exposed corneal and conjunctival tissues. The patient should be advised to avoid environmental conditions that encourage evaporation of their tears (e.g., ceiling fans, forced air heaters, wind, etc.).