Glaucoma in Thyroid Eye Disease

320 King and Netland

Table 1 Prevalence (%) of Ocular Hypertension in Patients with Graves’ Disease and in the General Population

Graves’ General

disease population

(%)(%)

the chronic phase of Graves’ ophthalmopathy, there may be marked orbital infiltrative congestion characterized by hypertrophy of the extraocular muscles and orbital fat (12). This congestion may raise the retrobulbar pressure to levels that can compress more compliant structures such as the ophthalmic veins, and lead to raised episcleral venous pressure and, hence, elevated intraocular pressures (4,5).

Other mechanisms may contribute to the elevated intraocular pressure observed in patients with Graves’ disease. These patients may accumulate mucopolysaccharide deposits in the aqueous outflow network, which could reduce the outflow facility and lead to increased intraocular pressures (13). It has been reported that corneal exposure can cause a severe anterior chamber reaction, which in turn may cause peripheral anterior synechiae formation associated with glaucoma (4,13,14).

III.RELATIONSHIP BETWEEN GRAVES’ DISEASE AND OCULAR HYPERTENSION OR GLAUCOMA

The association between Graves’ disease and elevated intraocular pressure has been demonstrated in several studies (15–23) (Table 1). In a prospective study of 104 consecutive Japanese patients with Graves’ disease, 22% (23 patients) had ocular hypertension, which is higher than the 1.37% prevalence of ocular hypertension in the general Japanese population (23). A retrospective study of 482 patients with Graves’ ophthalmopathy showed 3.9% with ocular hypertension compared with 1.6% in the general population (22). A retrospective study of 500 consecutive patients with thyroid-associated ophthalmopathy from Pittsburgh’s Allegheny General Hospital showed 24% with ocular hypertension compared with 5% in the general public (15). The prevalence of ocular hypertension in patients with Graves’ disease has been found to range between 5 and 15% (16–20). Some studies have found positive correlation between the degree of proptosis and the level of ocular tension (24). In contrast, several studies have found no increased prevalence of ocular hypertension in patients with Graves’ disease compared with the general population (25–27).

The prevalence of open-angle glaucoma in patients with Graves’ disease is similar to that in the general population (15,22,26). In a study of 500 patients with thyroid eye

disease, only 7 patients were classified as glaucoma subjects, and 2 patients showed progressive visual field abnormalities and cupping (15). However, a prospective Japanese study found a higher prevalence of open-angle glaucoma in patients with Graves’ disease than would be expected based on comparison to the general population in Japan (23).

IV. CLINICAL EXAMINATION

During the clinical examination of patients with thyroid eye disease, there are some unique points to consider. Applanation tonometry may be performed in primary gaze, upgaze, and downgaze. With fibrosis of the inferior rectus muscles, intraocular pressure may be lower in downgaze and elevated in upgaze. A greater than 2 mmHg increase on upgaze is often considered abnormal; however, healthy individuals may show an increased intraocular pressure of 4–6 mmHg in different gaze positions (9). It may be helpful to note an increased intraocular pressure in upgaze, but this finding is nonspecific in patients with thyroid eye disease (10).

Raised episcleral venous pressure is characterized by dilated, tortuous episcleral veins. Measurement of episcleral venous pressure is not commonly performed clinically. However, observation of dilated and congested episcleral vessels should be noted.

Optic nerve examination should be performed to assess the size, appearance, and integrity of the optic disc. Visual fields should be performed to correlate the appearance of the optic nerve with glaucomatous visual field defects. On the other hand, in particular with optic neuropathy due to Graves’ disease, the appearance of the optic nerve may be normal or disc edema may be found (28). In general, the appearance of the visual field does not correlate well with optic nerve appearance in compressive or infiltrative optic neuropathy due to thyroid eye disease.

V. MANAGEMENT

Management of elevated intraocular pressure in patients with concomitant glaucoma and thyroid ophthalmopathy may be influenced by the treatment of the thyroid eye disease. Corticosteroid therapy may suppress orbital inflammation, which may have a beneficial effect on intraocular pressure (5), although chronic steroid therapy may contribute to a rise in intraocular pressure (29).

A number of studies demonstrate a significant reduction in intraocular pressure after decompression of the orbit (14,22,24). Furthermore, Kallman documented two cases in which patients with Graves’ orbitopathy and elevated intraocular pressure showed a marked reduction in intraocular pressure, after recession of the inferior rectus muscles (22). He also noted that five patients with Graves’ orbitopathy and ocular hypertension showed a permanent decrease in intraocular pressure after orbital decompression (22). A retrospective evaluation of 12 consecutive patients (22 eyes) with thyroid orbitopathy who underwent surgical decompression showed significantly lower intraocular pressure postoperatively than preoperatively. These results were attributed to the reduction in orbital pressure and subsequent reduction of episcleral venous pressure (14). Algvere reported that three of five patients with both thyroid eye disease and intraocular pressures of 28 mmHg or higher, which were all refractory to medical therapy, showed remarkably lower intraocular pressures not requiring further medical therapy after orbital decompres-

sion was performed (17). Orbital decompression surgery should be performed, when necessary, before consideration of surgical procedures for the correction of glaucoma.

A.Medical Management of Elevated Intraocular Pressure

Gaze-dependent ocular hypertension should be differentiated from sustained pressures in any direction of gaze. Treatment is usually not indicated for infiltrative ophthalmopathy with elevated intraocular pressure in some gaze positions. However, patients with sustained high ocular tension, especially in primary gaze position, may require treatment.

Topical antiglaucoma medications should be the first line of approach, in particular aqueous suppressants. In patients with elevated episcleral venous pressure, cholinergic drugs may have minimal effects; aqueous humor suppression using beta-adrenergic blockers, alpha-adrenergic blockers, and carbonic anhydrase inhibitors may yield better results. Prostaglandin analogues may be associated with ocular inflammation, which should be avoided during the acute congestive phase of thyroid ophthalmopathy.

B.Surgical Intervention

Laser trabeculoplasty may not be effective in lowering intraocular pressure associated with elevated episcleral venous pressure.

Filtration surgery with adjunctive antifibrosis drugs is an effective and commonly used treatment for patients with glaucoma that has failed to respond to medical and laser therapy. However, patients with Graves’ ophthalmopathy associated with elevated episcleral venous pressure may have an increased risk for choroidal effusion and suprachoroidal hemorrhage (30). These complications can be minimized with tight closure of the scleral flap with releasable sutures or the use of postoperative laser suture lysis. Cyclophotocoagulation may provide an alternative to filtration surgery in some cases in which elevated intraocular pressure is secondary to elevated episcleral venous pressure.

VI. HYPOTHYROIDISM

In 1920, Hertel noted an association between hypothyroidism and primary open-angle glaucoma in two patients (31). Since that time, other case reports and studies have found an association of hypothyroidism with primary open-angle glaucoma (32–35). Myxedema is a severe form of hypothyroidism in which, through autoimmune processes, mucopolysaccharides accumulate in the ground substance of various tissues. It has been suggested that the trabecular meshwork could be obstructed through this mechanism (32,36). Hypothyroid patients have been found to have reduced facility of outflow, which improved with treatment of the hypothyroid state (33,37). Others have found no evidence of an association with hypothyroidism and primary open-angle glaucoma (27,38).

Some early reports note an association between hypothyroidism and a high–normal elevated intraocular pressure (31,39–42). Other studies, however, have not shown the same relationship (26,27,43).

VII. CONCLUSION

Elevated intraocular pressure is more commonly found in patients with thyroid eye disease than in the general population. However, definite glaucomatous progressive changes of the

optic nerve and visual fields are probably no more common than in the general population. Treatment for Graves’ orbitopathy, particularly orbital decompression, may have a beneficial effect on the intraocular pressure. Patients with elevated intraocular pressure should be monitored for optic nerve and visual field changes. Medical antiglaucoma therapy may be required, but surgical treatment for glaucoma is not necessary in the majority of patients with thyroid ophthalmopathy and elevated intraocular pressure.

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Figure 2 Moderate disk edema and peripapillary nerve fiber layer hemorrhage of the right eye in a patient with optic neuropathy of Graves.

been described, including central scotoma, paracentral scotoma, arcuate and nerve fiber bundle defects, increased blind spot size, and generalized constriction (2,3) (Fig. 1). Threshold visual field is recommended in routine screening of patients with severe Graves’ disease and in those patients who present with visual symptoms.

The optic disk may appear entirely normal in thyroid optic neuropathy. Changes include mild or marked disc edema (Figs. 2, 3) and pallor, which have been observed in approximately half of affected patients (2,3,6). No special features of the optic disk swelling are considered pathognomonic for compressive optic neuropathy. Congestive signs and evidence of ocular myopathy almost always precede visual loss, which is often bilateral,

Figure 3 Moderate disk edema of the left eye in a patient with optic neuropathy of Graves.

symmetrical, and gradual in onset. Presentation may be limited to one eye in 24–40% of cases (2,6,7).

Electrophysiological evidence of compressive thyroid optic neuropathy may be provided by a visual evoked potential (VEP). VEP abnormality, specifically prolonged P100 latency, is a sensitive indicator of an optic nerve conduction defect, which may be documented in more than 90% of patients (3,8). The VEP abnormality may be present in patients without subjective vision complaints or clinical evidence of optic neuropathy (9).

III. PATHOGENESIS

The pathogenesis of thyroid optic neuropathy remains somewhat controversial, but it is most likely related to mechanical compression of the optic nerve at the orbital apex (6). Inflammatory cellular infiltration, mucopolysaccharide deposition, and interstitial edema develop in the orbital tissues, including the extraocular muscles (10). Compression of the optic nerve may result from increased intraorbital pressure resulting from these changes, or to thickening of the extraocular muscles at the orbital apex, where the limited crosssectional area may add to a compressive effect (11). Either direct damage or indirect damage through an ischemic effect may result from mechanical compression of the optic nerve (2). Trokel and Jakobiec (11) noted that compression from enlarged extraocular muscles can lead to impedance of venous drainage of the orbit and thereby cause venous stasis and orbital congestion. Nugent et al. (12) demonstrated an enlarged superior ophthalmic vein that they found to be more common in orbits with concomitant optic neuropathy. They interpreted this as a reflection of apical compression by the enlarged extraocular muscles.

Recent advances in imaging techniques have greatly improved visualization of the pathological soft tissue changes of thyroid ophthalmopathy. Standard A-scan ultrasonography notes enlargement of the bellies of the extraocular muscles with the insertions relatively spared. A medium to highly reflective internal interface within the muscles is characteristic of Graves’ disease (13). B-scan ultrasound documents the qualitative increase in the diameter of the muscles; however, muscle enlargement at the apex of the orbit is difficult to assess (6). Ultrasonography may also demonstrate evidence of optic nerve enlargement with increased subarachnoid fluid surrounding the anterior portion of the optic nerve (14,15).

Computed tomographic (CT) scanners are capable of generating two-dimensional images with high resolution and minimal volume averaging. Axial and coronal scans should be obtained in patients with severe thyroid eye disease who are suspected of having optic neuropathy. Enlargement of the extraocular muscles with relative sparing of the tendinous insertion is the most frequent finding (Fig. 4). Coronal views frequently document enlarged extraocular muscles converging at the crowded orbital apex with compression of the optic nerve (Fig. 5) (11). Neigel and co-workers (3) noted apical crowding of moderate or severe nature in 79.2% of patients with thyroid optic neuropathy. In more than half of these patients the optic nerve appearance at or near the orbital apex was flattened or decreased in size secondary to compression from the enlarged extraocular muscles. Other findings noted on CT scans include proptosis, prominence of orbital fat, anterior displacement of the lacrimal glands, dilated superior ophthalmic vein, and stretching of the optic nerve (3,6,11,16).

Some investigators have determined that proptosis is not helpful in assessing the risk of optic neuropathy, but rather extraocular muscle volume shown by limitation of

a factor with MRI. However, MRI scans are more expensive, less readily available, and take a longer period of time. Optimal orbital scans are obtained by the use of a surface coil with fat suppression.

IV. THERAPY

Although spontaneous remission of untreated thyroid optic neuropathy has been reported with a favorable outcome, nearly one-quarter of reported patients remain severely visually impaired (18). Previously reported series of patients with thyroid optic neuropathy (2,7,19) indicated that oral systemic corticosteroid therapy could be of benefit, although relapses occurred in a significant number of patients as the corticosteroid dosage was lowered. The mechanism for steroid therapy is uncertain, although the anti-inflammatory and immunesuppressive actions are probably the most important.

There are no firm guidelines to systemic steroid dosage in thyroid optic neuropathy. Most clinicians prescribe oral corticosteroids in dosages of 60–100 mg/day prednisone for 2–4 weeks, with a gradual tapering by 5–10 mg/day every 1–2 weeks. Trobe and associates (2) noted that if a response to oral corticosteroids was to occur at all, signs of improvement in visual function were evident within 1 week or earlier. They considered that there was no apparent justification for maintaining patients with optic neuropathy on prolonged corticosteroid therapy in the absence of improvement. If an observable response has not occurred within 3 weeks, continued high dosage is not likely to be successful.

Some clinicians have advocated intravenous methylprednisolone in dosages similar to those given patients with other autoimmune diseases, such as lupus erythematosus. Methylprednisolone, 500 mg–1.0 g daily for 3 days, may be used. This therapy may provide a more rapid response of thyroid optic neuropathy that may be sustained by a tapering regimen of oral corticosteroids and/or orbital irradiation (20).

The efficacy of oral prednisone, as compiled by Wiersinga from eight studies published between 1955 and 1993, was 65% (21). In patients with poor response to therapy, with considerable side effects to therapy, or requiring high-dosage corticosteroids for control, alternative radiation therapy or surgery should be considered. Almost all patients on long-term corticosteroid therapy experience side effects, which limit the duration of therapy. If radiation or surgery is considered, the corticosteroid may be continued and its dosage tapered during and following radiation therapy or in the postoperative period.

A.Radiation

External beam irradiation should be considered for patients with thyroid optic neuropathy in whom corticosteroids are contraindicated, for those who experience significant side effects from corticosteroids, and for those who are nonresponsive after an adequate trial. Patients who require surgical decompression for thyroid optic neuropathy and whose inflammatory features continue may also be candidates for radiation therapy (22). Although it is not clear why radiation therapy is effective in Graves’ disease, it may be that there is a differential effect on helper and suppressor T lymphocytes. Whether radiation therapy is simply an immunosuppressive mediator affecting specific lymphocytes or acts by diminishing the inflammatory response nonspecifically is still unknown (22).

The recommended dose of radiation is 2000 cGy. An oral corticosteroid may be continued, at least during the first 2 weeks of radiation therapy. A response should be evident within 2 weeks of completion of therapy, and progressive neuropathy 4 weeks or

more after radiation indicates a need for alternative therapy (23). Radiation is not indicated for patients with coexistent diabetic retinopathy or with previous cranial radiation.

Kazim reported that 95% of patients treated for thyroid optic neuropathy with radiation experienced improvement. Only 1 of 29 patients treated with radiotherapy required surgical decompression (1). Rush and colleagues reported improvement in optic nerve function in 8 of 10 patients during radiotherapy (2000 cGy in 10 fractions) or within 2 weeks of completion (24).

B.Surgical Decompression

Garrity and co-workers (25) have noted that primary therapy of thyroid ophthalmopathy is directed toward resolution of the volume to space discrepancy. The volume to space discrepancy can be resolved medically by shrinkage of soft tissues with corticosteroids or radiation or by expanding the orbital volume surgically to accommodate the swollen tissue.

The value of surgical decompression in preserving vision in patients with thyroid optic neuropathy has been documented in several studies (25–29). However, prognosis for vision return in such patients with chronic poor vision is guarded after any form of therapy (30). In patients with compressive optic neuropathy unresponsive to corticosteroid therapy and/or radiation therapy, surgical decompression is recommended, unless there is an absence of clinical and CT evidence of enlarged extraocular muscles and optic nerve compression. In patients with rapid (less than 1 week) vision loss, relatively rapid progression of vision loss to less than 20/200, or marked vision loss secondary to rapid proptosis, emergent decompression with simultaneous high-dosage systemic steroid therapy should be considered (30).

Orbital decompression can relieve the apical compression and offer a more rapid response than medical or radiation therapy. Response can be measured postoperatively by improvement in visual acuity and improvement or resolution of visual field defects and dyschromatopsia. Disk edema observed preoperatively should resolve (25). Since surgical decompression does not affect the cause of inflammation or fibrosis of thyroid ophthalmopathy, these patients may require further treatment in the postoperative period to preserve vision. McCord noted that 27% of patients required additional therapy after surgical decompression and 20% required supplemental steroids or irradiation (27).

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vision, or reduced color perception should be elicited. Patients are often keenly aware of the physical changes in their anatomy, describing a ‘‘wide eye,’’ ‘‘bulging,’’ or ‘‘staring’’ appearance to their globes. Often these patients are aware that their eyelids do not fully close, especially at night, or they may simply complain of excessive ocular surface irritation on awakening. Patients with increased orbital congestion may complain of periocular soft tissue swelling or increased orbital pressure that they dismiss as a nonspecific allergic reaction. Dry eye symptoms are common and may include foreign body sensation, itching, excessive mucus secretion, heaviness of the eyelids, sensitivity to light, pain, redness, burning, and blurred vision either with or without monocular diplopia. The patient should be questioned as to whether each of these perceived changes is experienced as stable or progressive.

A careful review of both prescription and over-the-counter medications is essential and may reveal both topical and systemic drugs that should be avoided in patients suspected of having TED. Specifically, common medications that can exacerbate an already dry eye should be avoided. Examples of such medications include antiallergy sinus medications, blood pressure medications, antidepressants, diuretics, and topical vasoconstrictors such as Visine.

If TED is suspected, but systemic disease has not been established, a careful review of the patient’s past medical history and a detailed review of systems are in order. Any history of thyroid gland dysfunction, pretibial edema, or phalangeal acropachy should be recorded. Symptoms suggesting systemic thyroid hormone dysfunction such as heart palpitations, weight change, mood disturbance, and temperature disturbance should be elicited. A review of the patient’s family history may reveal relatives with dysthyroid states or autoimmune diseases. A complete social history should include the use of tobacco products, as tobacco has been identified as a risk factor for a more severe course of ophthalmic disease.

B.Examination

The physical examination in patients suspected of having thyroid eye disease must include documentation of best-corrected visual acuity. The Snellen notation is the most common method of expressing visual acuity measurement and is measured monocularly, both at distance and near, after correcting for any errors in refraction.

In addition to visual acuity disturbance, decreased color vision, disruption in the normal pupillary light reaction, and disturbances in the field of vision are indicative of optic nerve dysfunction seen in compressive optic neuropathy. Color vision disturbance may be detected by a relative desaturation in the color red in one eye as compared to the other. Color vision can be tested with pseudoisochromatic color plates. Patients with normal color vision can easily detect specific numbers and figures composed of and embedded in the dot patterns on these plates, but patients with impaired color vision may not detect these same symbols or numbers. Another test of color vision, the 15-hue test (Farnsworth-Munsell D-15 test), consists of 15 pastel-colored chips, which the patient must arrange in a related color sequence. The sequence is obvious to patients with normal color vision, but patients with color deficits may arrange these chips differently.

Pupillary examination with documentation of the relative reaction of both pupils to light should be recorded. A relative afferent pupillary defect is detected with the so-called

swinging flashlight test. Normally, the pupillary reaction to light should be equal in both eyes; with compressive optic neuropathy, the normal afferent pupil response in inhibited and the pupil’s response to light is impaired. Careful observation should be used to quantify the defect and evaluate it over time.

Visual fields are also used to assess optic nerve function. Confrontational visual fields are important, but do not substitute for a formal assessment of peripheral vision using static automated perimetry (Humphry, Octopus) or kinetic perimetry testing (Goldmann or tangent screen). Perimetry is used to both confirm and quantify a visual field defect and then to follow its progression over time.

Restrictive myopathy in TED is best detected by examination of the eyes in each of the six cardinal positions of gaze (right, up and right, down and right, left, up and left, down and left) as well as indirect up and downgaze. Forced duction testing may be used to confirm the restrictive nature of any existing ocular misalignment and the amount of strabismus can be measured with the use of prisms and then quantified in prism diopters.

Examination of the periocular structures should include notation of any soft tissue inflammation, lagophthalmos, and lid lag in downgaze. Palpebral fissure heights and levator function should be noted. Superior and inferior scleral show, plus the distance of a light reflex to the upper and lower lid margin, should be documented. External photographs are extremely helpful for comparison to possible future changes. Exophthalmomometry using a Hertel exophthalmometer or similar device can be used to assess for proptosis. Although variations appear based on patients’ gender and race, a difference of more than 2 mm is considered abnormal.

Slit-lamp examination should include assessment for dilated vessels over the insertion sites of the extraocular muscles and presence of chemosis, as either finding may be suggestive of increased orbital congestion. The presence of filaments over the superior bulbar conjunctiva and superior corneal limbus suggests superior limbic keratoconjunctivitis. Fluorescein and rose bengal dyes are useful to highlight any breakdown in the corneal epithelium and to assess tear breakup time. Assessment of the amount of aqueous tears produced in 5 min after the administration of topical anesthesia should be recorded. Such a test can establish basal tear production in the absence of stimulation by the corneal sensitivity reflex.

Intraocular pressures (IOP) should be assessed in both downgaze and upgaze in order to rule-out artificial elevations of IOP caused by transient increased traction on the globe by a fibrotic inferior rectus muscle. True elevations in intraocular pressures should be managed with appropriate topical glaucomalytic agents. A dilated funduscopic examination is used to assess adequately the optic nerve head for increased cupping, pallor, or edema suggestive of optic nerve compression. Dilation will allow visualization of engorged retinal vessels suggesting orbital congestion, or the presence of chorioretinal folds suggesting orbital crowding.

Radiographic or ultrasound studies may occasionally be necessary to assess for progressive crowding within the orbit or document impingement of the optic nerve. If active orbital inflammation is suspected, routine ophthalmic evaluation should be repeated every 3–6 months to assist the patient in the management of their symptoms and to rule out onset of vision threatening disease. Patients who demonstrate stable findings for 12–24 months can be reassured that their orbital disease has most likely stabilized. Annual examination is recommended for patients at risk for TED, but show no evidence of orbital involvement on initial examination.

III. MEDICAL INTERVENTION

Therapeutic medical intervention in TED has three goals: continuing localized ophthalmic protective measures against corneal epithelial breakdown, management of diplopia in patients with either active or stable TED, and anti-inflammatory treatment of acute orbital inflammation and compressive optic neuropathy.

A.Dry Eye Syndrome

Decreased aqueous tear levels that result in dry eye are common in GAO. A relative tear deficiency results from a combination of excess in tear evaporation due to widened palpebral fissues, inhibited blink response, and proptosis. Inflammatory infiltration of the lacrimal gland and/or accessory lacrimal glands might also contribute to a decrease in tears in TED.

First, a person with dry eye should avoid anything that may cause dryness, such as an overly warm room, hair dryers, or the wind. Smoking is especially bothersome. Sunglasses and nocturnal taping of the eyes may be a helpful adjuvant to therapy. The next step in the treatment of decreased aqueous tear production is the addition of tear substitutes. Tear replacement by topical artificial tears remains the most widely used therapeutic modality in the treatment of dry-eye syndrome, and many cases, is the only treatment required. Artificial tears are available without a prescription. There are many brands on the market and each is slightly different. Patients may find one brand more effective than another. The exact frequency of administration of these medications varies: once or twice a day or as often as several times an hour.

Most commercially available artificial tear preparations contain preservatives that may be toxic to the ocular surface, particularly with prolonged use. Such preparations should be avoided in any eye that requires use of drops more than four times daily to maintain comfort. A number of nonpreserved lubricating eye drops and ointments are commercially available. In many cases of moderate to severe dry eye, the frequent application of nonpreserved lubricating drops with bedtime application of lubricating ointment is sufficient. In severe cases of dry eye, especially if associated with very high levels of tear osmolarity or poor eyelid closure, it sometimes is necessary to use lubricating ointment or gels throughout the day, despite their potential for blurring of vision. Solid artificial tear inserts placed inside the lower lid on a daily basis gradually release lubricants and are available by prescription. These may be beneficial to patients unable or unwilling to apply topical artificial tears on a frequent basis.

The retention of the aqueous tear film by punctal occlusion is also therapeutic for dry eyes. Punctal occlusion reduces tear film osmolarity, increases tear volume, and prolongs the residence time of externally applied tear substitutes. For patients who are using tear substitutes, punctal occlusion reduces the frequency of application required to obtain a desirable result.

Punctal occlusion may be permanent or temporary. Temporary occlusion may be achieved by insertion of collagen implants into the canaliculi or silicone plugs into the punctal opening. Permanent occlusion can be accomplished with thermal or electrical cauterization of the puncta and canaliculi, by argon laser photocoagulation of the punctum, or by insertion of silicone plugs into the punctal opening. Silicone plugs are preferred because they may be easily removed if symptoms of ephiphora occur.

The ability of high ambient humidity to retard evaporation and thereby preserve tear volume and reduce osmolarity can be achieved with the use of room humidifiers or

with moist chamber spectacles or goggles. The role of a moisture chamber is to minimize significantly the airflow over the ocular surface by use of a transparent barrier that functions passively to prevent tear evaporation by creating a sealed chamber around the patient’s eyes. Prescription medications can occasionally be of help for dry eye syndrome. Vitamin A supplements, topical steroids, and topical cyclosporine 0.05–0.1% may be helpful in patients who have exhausted other forms of therapy. Oral cholinergic agonists such as Evoxac (cevimeline, Daiichi pharmaceuticals) 30 mg three times daily and Saligen (pilocarpine, MGI Pharma) 5 mg four times daily to stimulate tear secretion by the lacrimal gland have, in the experience of this author, recently proven to be an effective therapy for dry eyes in TED.

In addition to dry eye management, the vast majority of patients experiencing active TED will require only palliative measures to increase comfort when active inflammation occurs. Assistance with smoking cessation is important, as tobacco use has been implicated as an exacerbating factor in TED. When periorbital edema secondary to TED occurs, it is important to reinforce practices that will minimize its fluid collection in the periocular tissue. Practical advice such as sleeping with the head propped up at least 30 degrees and applying ice packs daily to both eyes may be quite helpful in masking inflammatory signs. At least some studies also report that prescription diuretics may be effective in decreasing periorbital edema (1). This author has found that systemic nonsteroidal anti-inflammatory agents are effective in minimizing soft tissue swelling and decreasing subjective complaints of increased orbital pressure.

B.Superior Limbic Keratoconjunctivitis

Superior limbic keratoconjunctivitis (SLK) is a chronic recurrent condition of ocular irritation and redness thought to result from mechanical trauma to the superior bulbar and tarsal conjunctiva. It has been shown to occur in association with Graves’ disease (2).

SLK is characterized by the following features: inflammation of the superior tarsal conjunctiva in the form of a papillary conjunctivitis, inflammation of the superior bulbar conjunctiva, fine punctate staining with rose bengal and fluorescein of the cornea near the superior limbus, proliferation of superior limbic epithelial cells with micropannus formation, and filaments of the upper cornea and limbus. A stringy mucoid discharge is sometimes present and is associated with increase in severity of symptoms.

Symptoms tend to vary in severity with time, with activity, and generally coincide with clinical signs. The disease is painful and the pain develops as the day progresses, usually reaching its maximum in a working individual in the late afternoon. It seldom interferes with sleep and is usually at its best on awakening. Discomfort is greatly increased by the presence of limbal or corneal filaments. These filaments are associated with intense foreign body sensation and blepharospasm that lead to a vicious circle of pain, spasm, increased conjunctival hyperemia, mucus secretion, and further filament formation.

The classic treatment for SLK has been the local application of 0.5%–1% silver nitrate to the superior palpebral conjunctiva. This usually results in relief of symptoms for 4–6 weeks and may be repeated every 4–6 weeks without any untoward effects. The use of lubricants, topical vitamin A, n-acetylcysteine, pressure patching, bandage contact lenses, and botulinum toxin injections in the region of the superior orbital portion of the orbicularis muscle are reasonable options for treatment. Thermal cauterization and conjunctival resection have proved effective in patients with refractory disease (3,4,34–40).

C.Eyelid Retraction

The use of topical and systemic sympatholytic agents is based on the belief that Mu¨ller’s muscle overaction, at least initially, plays a significant role in eyelid retraction seen in TED. Although an increased sympathetic tone in the hyperthyroid state has never been proven, some physicians have used topical sympatholytics and systemic beta blockers with varying reports of success in an attempt to control the early noninfiltrative manifestations of TED such as stare, lid lag, or lid retraction (5). In theory such agents would only be effective early in the course of the disease, before the fibrotic phase of lid retraction begins (6). Such sympatholytic agents would theoretically create a postganglionic Horner’s syndrome that, at least in theory, counteracts the lid retraction by producing mild ptosis. Guanethidine sulfate 5% eye drops, a topical alpha-adrenergic blocker administered three times daily, as well as similar agents such as bethandidine, and thymoxamine have been used (7,8). Time has shown that these agents have worked only temporarily, if at all, and are often irritating to the ocular surface. Other side effects include miosis, conjunctival injection, punctate keratitis, and discomfort on administration of the drop (9,10). Because of their limited effect and because the indication for use has never been approved by the Food and Drug Administration, this class of drugs is seldom used in the modern management of TED. More recently, local injection of botulinum A toxin has also been used as a nonsurgical means of treating TED-associated eyelid retraction. However, the temporary effect of this agent, and its potential side effects (significant ptosis and relative superior rectus palsy with diplopia), make botulinum A toxin a suboptimal mode of long-term correction of TED-associated eyelid malposition (11).

D.Diplopia

The nonsurgical management of double vision associated with TED ranges from the simple occlusion of the eye with greater restriction of motility to the more complex prescribing of prisms. Many patients are opposed to wearing an eye patch for occlusion. One simple alternative is to opacify one lens in a pair of spectacles using an opaque adhesive tape. A variation in this technique, termed sector occlusion, involves use of a piece of translucent adhesive paper applied to the posterior surface of a lens or lenses in order to obstruct vision in a particular direction, thus preserving binocular vision in nonrestricted fields of gaze (12).

Prisms may be very useful in the treatment of certain patients who have a small degree of strabismus, but fitting of these prisms may be time-consuming and prone to trial and error. The amount of prism to give a patient for comfortable single binocular vision may be assumed arbitrarily to be one-third to one-half of the maximal phoria obtained on cover testing, or it may be titrated to the subjective response of the patient.

Temporary ‘‘stick-on’’ prisms are particularly useful during active orbital inflammation and in the immediate postoperative period when frequent variability in the degree and nature of diplopia is common. Laying a series of small prisms adjacent to each other on a thin platform of plastic produces a so-called Fresnel prism. Fresnel developed these prisms in 1822 and Jampolsky and colleagues first described the use of paste-on membrane prisms made of flexible polyvinyl chloride in 1971 (13).

Such prisms can be used as a permanent prescription or as a temporary measure when there is uncertainty as to the prism correction, especially when the strabismic condition is variable or when recovery is expected. These membrane prisms are obtained easily, relatively inexpensive, and are easy to adjust in strength. Their disadvantages are that they

are somewhat dysesthetic, tend to yellow with age, and peel after about 3 months in place. Also, they do degrade acuity by about one line per every five-prism diopters. They are available in the ranges of 1–30 diopters, and may be confined to one lens, trimmed to fit a bifocal segment, distance correction, or part of the field of a lens, or prescribed in an oblique axis orientation for those patients who have both horizontal and vertical deviations.

Once the degree of strabismus stabilizes, the prism power can be permanently ground into the patient’s spectacle, eliminating the impact on vision by the plastic prisms. Studies analyzing the success rate of prism therapy in TED are limited, but Flanders et al. report at least temporary relief of diplopia in 17 of 18 TED patients treated with Fresnel prisms (13).

IV. IMMUNOSUPPRESSION

As mentioned above, in the majority of patients with TED the ocular findings are selflimiting and can be relieved by local therapies. In approximately one-third of all patients with GAO, eye signs will become sufficiently disabling or disfiguring to warrant further treatment with systemic immunosuppression. The aim of immunosuppressive treatment is to avoid surgery altogether, or to decrease the activity of the inflammation in order to improve surgical outcomes (14).

Before considering immunosuppression, it is useful to attempt to identify those patients most likely to respond. Up to 35% of patients with TED treated with systemic immunosuppression will show no significant response. The most likely explanation for this is that only patients with active orbital inflammation respond significantly to immunosuppressive treatment, whereas patients with manifestations of chronic fibrotic end-stage TED do not. Thus, an adequate assessment of disease activity might be important in determining a potential response to systemic immunosuppressive therapy (14).

Several methods to identify active orbital inflammation and to assess for potential response to corticosteroids exist. Urinary GAG excretion levels, eye muscle echogenicity, orbital [111In] octreotide (octreoscan) uptake levels, relaxation times of extraocular muscles via magnetic resonance imaging, and somatostatin scintigraphy have been promising in assessing disease activity (14,22,31–33). A clinical activity score (CAS) based on four of the five classic signs of inflammation to assess for a potential response to systemic corticosteroids has been devised with a positive predictive value of 80%, and a negative predictive value 64% in potential steroid responders (23). The 10 items of the CAS are listed in Table 1 (23). Patients with four or more points (one point for each finding) have an increased likelihood of response to immunosuppression in TED.

Systemic glucocorticoids are the most common immunosuppressants used in the treatment of TED and have been used with good success since the 1950s. Although the beneficial effects of corticosteroid use are clear, the precise mechanisms by which corticosteroids decrease the orbitopathy remains poorly understood. These agents probably serve in multiple capacities by suppressing immune function and decreasing inflammation, such as interference with the function of T and B lymphocytes; through reduction in the recruitment of neutrophils, monocytes, and macrophages; by inhibition of the function of immunocompetent cells; by inhibition of the release of mediators including cytokines; and, finally, by decreasing GAG synthesis and secretion by orbital fibroblasts (15,16).

Any patient with evidence of compressive optic neuropathy should be considered for immediate steroid treatment. Relief of neuropathy is often obtainable and visual improvement is seen. However, relapse is common after discontinuation of corticosteroids

Table 1 Clinical Activity Score

Painful, oppressive feeling on or behind the globe, during the last 4 weeks Pain on attempted up, side, or down gaze during the last 4 weeks

Redness of eyelids

Diffuse redness of the conjunctiva, covering at least one quadrant Swelling of the eyelids

Chemosis Swollen caruncle

Increase of proptosis 2 mm during 1–3 months

Decrease of eye movements in any direction during 1–3 months

Decrease of visual acuity of more than 1 line on the Snellen chart during 1–3 months

The presence of four or more features is associated with an increased likelihood of response to immunosuppression therapy in TED.

and many patients may require additional treatment with either radiation or surgical orbital decompression to stabilize vision loss (17,18).

Any patient with acute severe orbital inflammation and congestion should also be considered for steroid treatment. Such patients present with significant chemosis, injection, and periorbital edema, and a course of systemic corticosteroids in these patients will often result in a dramatic improvement in acute symptoms within a matter of days. Corticosteroids have a proven beneficial effect on soft tissue swelling, and impaired visual acuity, whereas a significant effect on proptosis and ocular motility is still debated (14). During active orbital inflammation, and particularly during the active phase of extraocular myositis, early suppression of orbital inflammation by systemic corticosteroids may limit damage to extraocular muscles and decrease both the degree of proptosis and the risk of protracted diplopia caused by postinflammatory intramuscular fibrosis (19).

Finally, although it has been difficult to ascertain whether the treatment of an overactive thyroid gland affects the progression of the ophthalmic disease, some evidence suggests that eye findings worsen with at least one form of treatment of the hyperactive state: radioactive iodine therapy (15). Therefore any patient considered at high risk for worsening of TED during treatment with radioactive 131I should be offered systemic corticosteroids. Such high-risk features include smoking, high serum tetraiodothyronine concentration before treatment, high serum concentration of thyrotropin-receptor antibodies after treatment, and high serum concentrations of thyrotropin after treatment (15).

Oral glucocorticoids, when administered at high dosages (60–100 mg/day) for several days, followed by a slow taper over the subsequent weeks, can be effective in up to two-thirds of patients requiring immunosuppression (20). The rate at which corticosteroid dosage can be tapered will depend somewhat on the clinical response, but decreasing the daily dosage by 5–10 mg per week usually is a safe guideline. Unfortunately, at least some patients will develop a recurrence of symptoms during or upon completion of the steroid taper and will require long-term steroid use to prevent exacerbation of symptoms.

Whenever systemic corticosteroids are used, patients should be warned about the potential for adrenocortical insufficiency associated with steroid treatment. In the months following the withdrawal of long-term high-dose steroids, patients will require supplemental steroids in the event of trauma, surgery, or infection. Common side effects of corticosteroid use are listed in Table 2. Given these numerous side effects, it is preferable to limit the use of corticosteroids to a few months. Agents that protect against osteoporosis and

Table 2 Common Side Effects

of Systemic Glucocorticoid Use

Acne

Arthralgia

Avascular necrosis of the hip

Cataracts

Cushingoid features

Diabetes

Fluid retention

Glaucoma

Headache

Hirtsutism

Hypertension

Immunosuppression

Increased bruising

Increased appetite

Irregular heartbeat

Loss of libido

Menstrual irregularities

Mood disturbance

Osteoporosis

Paresthesias

Poor wound healing

Skin rash

Stomach ulcers

Weakness

Weight gain

gastric irritation should be considered. Vitamin D (10,000 units once weekly) and calcium carbonate (0.5 gs orally, three times daily) may be helpful in protecting bones; agents that decrease stomach acid production may be useful in protecting the gastric lining. If extended treatment is required, immunosuppressive therapy or radiotherapy should be considered as adjuvant treatments that may allow a decrease in the dosage of systemic steroids.

Local glucocorticoid therapy has been used in an attempt to avoid the systemic effects of steroids. Retrobulbar injection of steroids has been used occasionally in an attempt to treat locally the inflammation of TED while minimizing side effects. This treatment has not been proven to be as effective as systemic therapy in prospective studies and carries the added risk of injury to the globe (21). More recently, the use of intravenous methylprednisolone 1 g daily for 3 days followed by a rapid taper with prednisone has been advocated as an alternative form of corticosteroid treatment that may result in less morbidity. In the last 10 years, glucocorticoids have also been used intravenously, by the administration of methylprednisolone acetate (0.5–1.0 g) at different intervals. The cumulative dose of steroid ranges from 1 to 2 g in different studies (22). Although intravenous administration appears to have advantages over the oral administration in terms of effectiveness and possible side effects, this remains to be proven by randomized studies (22).

In addition to corticosteroids, a number of other immunosuppressive agents have been proposed to treat TED in steroid-resistant or steroid-intolerant patients. These include

cyclosporine, cyclophosphamide, azathioprine, and plasmapheresis (15). These agents are usually reserved for those rare patients whose disease fails to respond to or who cannot undergo standard treatment with corticosteroids, radiation, or surgery. The efficacy of some of these agents recently has come into question and the use of these medications has largely fallen out of favor (15).

Other than steroid therapy, cyclosporine is the immunosuppressive drug that has been most thoroughly evaluated in the management of TED. This drug affects both humoral and cell-mediated immune reactions by inhibiting cytotoxic T-cell activation and antigen presentation by monocytes and macrophages, and by inducing activation of T- suppressor cells and inhibiting production of cytokines (24).

Several reports have evaluated the effectiveness of cyclosporine administration in TED (21,24–26). Although initial reports showed a dramatic improvement in ocular findings of TED, these positive effects were not uniformly confirmed in later studies (21). The use of cyclosporine has been reported in several studies, but only two were randomized and controlled (27,28). The first of these studies indicated a lower efficacy of cyclosporine than prednisone as a single-agent treatment. The second study confirmed this finding, but did find evidence to suggest that a combination of cyclosporine and prednisone may be more effective than either treatment alone (27). Thus, the use of cyclosporine might be indicated in association with glucocorticoids in patients who are resistant to steroids alone and in whom the persistent disease activity warrants continuing medical intervention. Side effects of cyclosporine are significant, however, and nephrotoxicity is one of the chief complications observed. Hypertension, hepatic toxicity, gastrointestinal distress, and paresthesias also may occur. Therefore, cautious levels of this drug (less than 7.5 mg/kg/ day) are recommended (27,28).

Cyclophosphamide is an inactive cyclophosphamide ester of nitrogen mustard that is activated intracellularly by phosphamidase. Its biological activity resembles that of other polyfunctionally alkylating agents. It acts by selective depletion of activated B lymphocytes and inhibition of lymphocyte proliferation. Cyclophosphamide has been used for the treatment of TED since 1979 and its reported success rate is variable (29). No clinical trials have compared its efficacy to glucocorticoids. Cyclophosphamide 700 mg administered intravenously monthly for 1 year, or cyclophosphamide 85–150 mg/day in conjunction with corticosteroids, may help to decrease congestion and improve motility in some patients (29). However, because sterility occurs with administration of this medication, and its true efficacy is unclear, it should be reserved for patients whose disease has failed to respond to all other forms of therapy and who are no longer of child-bearing age. Other side effects of cyclophosphamide include leukopenia, alopecia, and hematuria.

Azathioprine 2 mg/kg/day over 2–3 months has been advocated as an alternative and/or adjunctivant to corticosteroid therapy in TED. Controlled studies, however have found azathiaprine to be ineffective in TED (29,30). For a time, plasmapheriesis was used in the treatment of TED, but it has not been proved to be beneficial (22). The rationale for the use of plasmapheresis in the treatment of TED was based on the assumption that this procedure might remove either immunoglobulins or immune complexes possibly involved in the pathogenesis of the disease. Thus far, studies examining the efficacy of plasmapheresis have provided conflicting results: both favorable effects and treatment failures were reported. No study on the effects of plasmapheresis was randomized and controlled, and the interpretation of results is made more difficult by the frequent concomitant or subsequent treatment with steroids or immunosuppressive drugs (22).

V. FUTURE TREATMENTS

New treatments for TED are already being developed. As our understanding of the cause of TED grows, future treatments will be developed to disrupt the mechanisms responsible for active orbital inflammation. Treatment of patients at risk for TED will also be developed that can halt the inflammatory process before the disfiguring and potentially visionthreatening complications ever begin.

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