NONMICROBIAL INFLAMMATION Many forms of inflammatory processes may trigger orbital inflammation that simulates neoplasms by producing proptosis

and associated orbital findings.82 These include Graves disease,83,84,85 idiopathic orbital inflammation (orbital pseudotumor),86,87 Tolosa-Hunt syndrome,88,89 sarcoidosis,90,91 Sjgren syndrome,92,93 and Wegener granulomatosis.94,95,96 Graves Disease Thyroid-associated orbitopathy, better known as Graves disease (Gd), is an idiopathic orbital inflammation that primarily involves the muscles and soft tissues of the orbit and the eyelids. The commonly involved muscles include inferior, medial, superior and lateral recti that cause swelling of the tissue leading to proptosis and eyelid retraction (Fig. 9). Gd is the most common cause of unilateral and bilateral proptosis in adults; although uncommonly it may be seen in children as well. Fig. 9. Graves disease. Clinical findings of Graves disease are depicted in frame A, including bilateral proptosis and lid lag with extraocular motility disturbance, chemosis with prolapse of lacrimal gland and congestion of conjunctival and episcleral blood vessels. Axial CT scan (B) reveals marked swelling of all recti muscles. The histopathologic appearance of the extraocular muscle from a patient with Graves disease reveals chronic inflammatory infiltrates, primarily composed of lymphocytes and plasma cells (C). The extraocular muscle volume is increased because of diffuse endomysial fibrosis, mucopolysacccharide deposition and chronic inflammatory cell infiltration (D). The orbital fat, meninges and the optic nerve (blue arrow), large blood vessels of the orbit, such as ophthalmic artery and its branches (green arrows) and the ciliary ganglion (red arrow) do not show any inflammation. The enlargement of the extraocular muscles are well depicted in frame E, which represents a transverse section, approximately at the level indicated by the yellow line in frame B. (LR: lateral rectus; SR + L: superior rectus and levator complex; SO: superior oblique; MR: medial rectus; IR: inferior rectus; IO: inferior oblique). (Frames C, D, and E are the courtesy of Ralph C. Eagle, MD of Philadelphia, PA) The pathogenesis of Gd is not completely understood; therefore, it is labeled as an autoimmune process.82,98 It has been suggested that individuals with HLA-B8 major histocompatility antigen Haplotype are genetically susceptible to Gd.99 The hypothesis is that circulating T-cells directed against an antigen in thyroid follicular cells recognize a similar antigen in extraocular muscles and orbital soft tissues.100 Experimental studies suggest that thyrotropin receptor (TSH-R) is one of the possible entities to stimulate the autoantibodies that lead to the inflammatory changes within orbital soft tissues. In Gd there is a predominance of Tcells with Th1 profile, although Th2 profile of cytokine production has also been reported.100 The cytokines stimulate fibroblasts to produce glycosaminoglycans that in turn lead to deposition of this substance within the muscle tissue leading to anatomic and functional deficiencies (Fig. 9). Although cell mediated immune reaction predominate in early Gd, humoral immunity plays a greater role in later phases.101 Some of the immune changes are reflected in the histopathology of Gd, which can basically be divided in two stages. The active inflammatory stage consists of perivascular edema and clustering of lymphocytes and plasma cells; lymphoid follicles are not frequent in Gd. In the chronic stage the volume of the involved orbital tissues are increased because of the deposition of glycoproteins and mucopolysaccharides and secondary to the infiltration of fibroblasts producing collagen. Later in chronic stages of the disease, the edema decreases and the muscles

are primarily infiltrated with interstitial fibroblasts and chronic inflammatory cells leading to fibrosis. Although 80% of patients with Gd present with a history of hyperthyroidism, approximately 10% suffer hypothyroidism or autoimmune thyroiditis; occasionally, an euthyhroid individual may also develop the signs and symptoms of Gd.102 Upper lid retraction is the most frequent clinical sign in early Gd (75%) followed by asymmetrical bilateral proptosis (60%) and restriction of extraocular muscles (40%). Compressive optic neuropathy may result secondary to the enlargement of the extraocular muscles in the apex. Optic nerve malfunction is manifested by afferent pupillary defects and color vision and visual field deficiencies in approximately 5% of Gd patients. The best means of evaluation of extraocular muscles is imaging with CT and/or MRI.11 Axial CT scan is very valuable to depict the enlargement of the extraocular muscles and determine whether there is any infiltration into other orbital soft tissues. Coronal sections are also very useful to evaluate the enlargement of the muscles and their relationship to the optic nerve in the orbital apex.103 In differential diagnosis of Gd, one should keep in mind that it is not only the most frequent cause of bilateral proptosis but unilateral proptosis as well. Therefore, the slowly progressive unilateral presentation may be confused with orbital pseudotumors, neoplasia, and solitary vascular lesions such as orbital varix.104,105 Orbital metastatic neoplasms may also be confusing if they are limited to the extraocular muscles. Imaging usually reveals nodular enlargement of the muscle and the diagnosis of a metastatic disease may be confirmed with fine needle aspiration biopsy (FNAB). The treatment of Gd includes oral and intravenous steroids, radiation and surgery.

Editors: Kertes, Peter J.; Johnson, T. Mark Title: Evidence-Based Eye Care, 1st Edition Copyright 2007 Lippincott Williams & Wilkins > Table of Contents > Section VIII - Oculoplastics > Chapter 15 - Thyroid Eye Disease Chapter 15 Thyroid Eye Disease Louise A. Mawn MD Thyroid eye disease (TED) is an immune-mediated inflammatory condition involving the soft tissues of the orbit. Although most commonly associated with hyperthyroidism, patients with low levels of thyroid hormone (hypothyroid) and even normal levels of thyroid hormone (euthyroid) can exhibit the clinical manifestations of TED. The overwhelming majority of patients with active Graves ophthalmopathy are hyperthyroid (>90%) and those who are euthyroid have thyroid autoantibodies on careful laboratory analysis.1,2 The onset of the eye changes occur within 18 months around the onset of hyperthyroidism.1,3 Graves ophthalmopathy is most commonly diagnosed at or within a year after the diagnosis of hyperthyroidism.4,5,6 Many similar terms such as thyrotoxic exophthalmos, endocrine exophthalmos, thyroid ophthalmopathy, or Graves ophthalmopathy are used to describe the condition.7 The weighted mean incidence of thyroid disease in the United States is estimated to be 13.9 per 100,000 per year.8 Up to 50% of patients with thyroid disease will develop overt eye changes, and a greater number will have subclinical ophthalmopathy and increased intraocular pressure.9,10 Bartley et al. studied the incidence of Graves ophthalmopathy in Olmstead County,

Minnesota.2 One hundred and twenty patients with Graves Disease were identified and used as the basis for several studies examining the chronology, clinical features, treatment, and longterm follow-up of Graves ophthalmopathy.2,4,11,12,13 The patients described by Bartley et al. were all white.2 Few studies examine nonCaucasian cohorts.14,15,16,17 Women are affected five times more frequently than men.2,5 Although most patients are middle aged, P.290 children and elderly individuals can also develop TED.1,2,18,19,20 Children make up <5% of patients with TED.2 Thyroid disease in children occurs more commonly in the teenage years.19,20 (see Fig. 15.1)

Figure 15.1 Seventeen-year-old girl with concurrent development of tachycardia, proptosis, and lid retraction who underwent elective total thyroidectomy for her hyperthyroidism. The clinical features seen in TED include lid retraction (Dalrymple sign), lateral flare of the upper lid, lid lag on downgaze (von Graefe sign), injection of the recti muscle insertions, proptosis, orbital congestion and inflammation, lid swelling, dry eyes, restriction of extraocular muscle movement and, in some cases, visual loss.7,12 Patients commonly complain of an orbital ache or pressure behind the eye or in the eye socket, photophobia, dry gritty eyes, tearing, double vision, and blurred vision. The eyes are not the only secondary organs involved in thyroid disease. Involvement of the skin can include inflammation over the tibia (pretibial myxedema or dermopathy) and thickening of the skin of the digits with digital clubbing (acropachy).21,22 Dermopathy and acropachy are associated with severe ophthalmopathy and are thought to result from a similar autoimmune mechanism.22 (see Fig. 15.2) The disease typically has an active phase in which the inflammatory component dominates and a late fibrotic component in which the late permanent effects of the previous orbital inflammation predominate. This curve of disease involvement was first described by Rundle in 1957 and is commonly referred to as Rundle's curve.23

Figure 15.2 Fifty-one-year-old man who smokes 1.5 packs of cigarettes per day complained of two and a half months of periorbital edema, double and blurred vision, rash on his legs, insomnia, weight loss of 18 pounds, fatigue, heat intolerance, leg pain, and irritability. Laboratory results were remarkable for free T4 of 2.24 (0.6 to 1.8 ng/dL), a suppressed TSH of 0.005 (0.3 to 5 U/mL) and markedly positive thyroid peroxidase antibodies at 3,928 (0 to 2 U/mL). P.291

Graves ophthalmopathy has a measured profound negative impact on patients' quality of life.24,25,26 The disease affects both physical and mental functioning, eroding self-confidence and socially isolating Graves ophthalmopathy patients.25,26,27 Facial disfigurement resulting from the lid retraction, eyelid swelling, and retraction in Graves disease is reliably recognized by lay persons, endocrinologists, ophthalmologists, and Graves ophthalmopathy patients.28 A Graves ophthalmopathy quality of life questionnaire, assessing both visual function and psychosocial function, developed in the Netherlands was first studied for validity and then used to assess improvement from treatment.27,29 In a prospective cohort study, this instrument showed a 10 to 20 point change after radiotherapy or decompression and a 3 to 10 point change after strabismus and lid surgery.30 The Dutch quality of life questionnaire was translated, slightly modified, and studied in Australian patients with Graves ophthalmopathy with similar findings.24 Both environmental and genetic features may influence the course of the disease. Cigarette smoking has been shown to be associated with a greater likelihood of developing TED in patients with thyroid disease.31,32,33,34 A summary of nine studies found an average of 67% (range 44% to 95%) prevalence of smokers among patients with Graves ophthalmopathy.35 Increased cigarette use has also been associated with more severe eye disease.34,36,37,38,39 The risk relationship between tobacco and Graves ophthalmopathy is not seen in former smokers with comparable lifetime tobacco consumption.34 In a European study of childhood Graves ophthalmopathy, prevalence of eye disease correlated with teenage smoking prevalence (p = 0.0001) in various countries.20 The strong relationship reported between current tobacco use and risk for TED argues that patients should be counselled to stop smoking.40,41 A prospective study of 155 newly diagnosed Graves disease patients showed a prevalence of Graves ophthalmopathy of 42% among Europeans and 7.7% for Asians (p = 0.0002). Twin studies have shown a higher incidence of thyroid disease.42,43 However, no specific genetic loci have been found and environmental factors may have a greater influence on the development of TED than genetic

factors.44 Radioactive iodine may also exacerbate TED activity, particularly in patients who smoke.45,46,47 The immune disorder is thought to be caused by antibodies directed toward the thyroidstimulating hormone (TSH) receptor.48 This receptor is common to the organs affected by thyroid disease.49 In thyroid disease, the antibodies to the TSH receptor lead to excess production of thyroid hormone.49,50,51,52 Eye changes result from the intraorbital inflammation and enlargement of the orbital adipose tissue and muscles.53 The orbit is invaded by CD4 + T cells.54,55 Cytokines amplify the reaction and cause fibroblasts to synthesize and secrete glycosaminoglycans. The orbital soft tissue volume increases both because of cytokinestimulated glycosaminoglycan accumulation within the extraocular muscles and adipogenesis.52,56 Systemic intervention is most likely to change the outcome in the early active phase of the TED; once the fibrotic phase has occurred, medical intervention is unlikely to improve the eye disease. Endocrine evaluation should be performed on all patients suspected of having TED. Laboratory studies should include TSH, tri-iodothyronine (T3), free thyroxine (FT4), and the thyroid antibodies including antithyroid peroxidase and antithyroglobulin. Imaging with computed tomography (CT) helps define the position of the globes in the bony orbit (particularly if the optic nerve is on stretch or if proptosis exists) and the size of the extraocular muscles and the relationship of the enlarged muscles to the optic nerve at the orbital apex (see Fig. 15.3). Considerable controversy exists regarding the treatment of TED. Medical Treatment of Systemic Thyroid Abnormality There are various methods for treating the systemic hyperthyroid disease. Most commonly the disease will first be treated with drugs that block thyroid hormone synthesis: Methimazole, carbimazole, and propylthiouracil through both a block and replace (higher dose antithyroid medication concurrent with thyroid hormone) method or a titration method (reduction based on thyroid hormone concentration).57 Two randomized prospective clinical trials showed progression of ophthalmopathy in some patients treated with radioactive iodine.45,58 This progression can be managed with steroid administration.45 A prospective, observational study of 72 patients examining radioiodine in minimally active Graves ophthalmopathy showed no change in TED when hypothyroidism was prevented.59 Because functional somatostatin receptors are expressed on activated lymphocytes and fibroblasts, somatostatin analogs have been considered as possible modulators of Graves ophthalmopathy. A double-blind placebo-controlled trial of octreotide P.292 long-acting repeatable (LAR) was studied in 50 euthyroid patients with active Graves ophthalmopathy. Patients received either 30 mg LAR every 4 weeks for 16 weeks or placebo. Both were followed by 30 mg for 16 to 32 weeks, and then no treatment for an additional 24 weeks. There was no significant difference in clinical outcomes between the groups.60

Figure 15.3 Axial computed tomography image at the midorbit level of two patients with Graves-related optic neuropathy. The image on the left shows stretching of the optic nerve from axial displacement by the increase in orbital fat. The image on the right shows enlarged recti muscles causing compression at the orbital apex. Medical Treatment of Orbitopathy Rundle described the course of Graves ophthalmopathy as first having a Bell-shaped active phase in which inflammation occurred and later a severity curve which plateaus with permanent fibrotic involvement.23 Studies examining treatment effects need to account for the natural tendency of Graves ophthalmopathy to improve with time. Only the active phase is expected to respond to immunosuppressive therapies. Steroids are used to decrease the complications of the active phase of the disease. Several randomized controlled trials (RCTs) address whether steroids shorten the duration of the active phase and improve the outcome. A randomized, prospective, open comparison of intravenous methylprednisolone versus oral prednisone in 33 patients with mild or moderate TED showed an insignificant difference but a trend of less additional treatment needed after intravenous steroid.61 A later study evaluated 70 euthyroid patients with various stages of Graves ophthalmopathy randomized to either once weekly intravenous methylprednisolone 0.5 g for 6 weeks and then 0.25 g for 6 weeks or oral prednisolone 0.1 g per day, tapering the dose by 0.01 g per week. Clinical signs such as proptosis, lid width, and diplopia were used as outcome measures. The patients treated with intravenous steroid achieved better results than the oral steroid group (p <0.01). Additional treatments were less frequently required in the intravenous group. Intravenous treatment was also associated with fewer adverse events than oral treatment (p <0.001).62 Smokers had worsening of ophthalmopathy in spite of steroids.62 Oral steroids were associated with >3 kg weight gain in 26%.62 A randomized trial comparing 19 patients treated with oral prednisone and 21 treated with immunoglobulin revealed side effects of steroids in 84% with severe hypertension and psychic disorders in two patients.63 A study of radiation therapy treatment with either oral or intravenous steroid showed greater steroid-related side effect in the oral steroid group (p <0.01).64 One of the possible deleterious effects of intravenous steroids is liver failure; the recommended cumulative dose of intravenous methylprednisolone is 6 to 8 g.65,66 Direct injection of steroids into the orbit has also been studied. A randomized prospective study compared 25 patients treated with 4 doses of 20 mg P.293

of triamcinolone acetate 40 mg per mL injected into the inferolateral quadrant versus no treatment controls. Patients with compressive ophthalmopathy were excluded. Motility (p = 0.0122) and the superior rectus levator complex size (p = 0.0060) significantly improved with the injections.67 Other immunosuppressive agents have been evaluated for treatment of Graves ophthalmopathy. Cyclosporine was compared to prednisone in a prospective, randomized masked study of 36 patients. Prednisone was associated with a better response but was not tolerated as well (p = 0.018). Combination therapy was effective in the patients who did not respond to either of the drugs used singly.68 A randomized study of 64 patients treated with antithyroid medication (28) or antithyroid medication and azathioprine (36) showed that only 1/36 patients treated with immunosuppression developed Graves ophthalmopathy as compared to the 7/28 treated with antithyroid medication alone. Four patients treated with azathioprine had gastrointestinal side effects or leucopenia69 Azathioprine was also used as a steroid-sparing drug in a case series study of 40 patients treated with radiation and immunosuppression.70 Steroid immunosuppression, both intravenous and oral, has been compared with irradiation and irradiation with concurrent steroid treatment. These studies are summarized in Table 15.1. Steroids and irradiation were shown in one study to be equally effective, though the steroid group had more short-term side effects.71 A combination of steroid and irradiation therapy was found to be more effective than either treatment modality alone.72,73 Medical treatment has also been compared with surgical treatment. Fifteen patients with active Graves ophthalmopathy and optic neuropathy were randomized to treatment with either surgical decompression (6) or intravenous methylprednisolone (9) for 2 weeks followed by oral prednisone for 4 months. Patients were switched to the other treatment if they did not improve with one. Immediate surgery did not result in improved outcome. This study was limited by the small number of patients.74 Irradiation for Thyroid Eye Disease Irradiation of the orbits in TED theoretically decreases the activity of the activated lymphocytes and fibroblasts.75 Radiation to treat Graves ophthalmopathy was initially directed to the pituitary as it was thought to be the source of an exophthalmic inducing factor.76 Potential side effects of radiation include cataracts, radiation retinopathy, and exacerbation of dry eye. Irradiation is contraindicated in patients at risk for retinal vascular disease such as patients with diabetes. Radiation has been considered as an alternative to immunosuppression with steroids. Several randomized prospective, placebo-controlled studies have conflicting conclusions regarding the benefit of radiation for TED (see Table 15.1). Mourtis et al. randomized 60 moderate Graves ophthalmopathy patients in the Netherlands to sham radiation or irradiation in a prospective double-blind study. The only significant result was better motility in the treated group; in spite of the improved motility, a similar number in the irradiated and placebo groups underwent strabismus surgery.77 Gorman et al. prospectively studied 42 patients at the Mayo Clinic, one orbit was irradiated, and then 6 months later the other control orbit was also irradiated. No benefit was found from irradiation.78 In a second study by the Netherlands group, patients in the early stage of mild disease were irradiated and compared with patients treated with sham irradiation; this study found no significant effect of the irradiation.79 All of these studies have limitations because of the difficulty in controlling for the disease phase.80 The median duration of eye disease in the Mayo study was 16 months.78 The Mayo study was most strongly criticized for treating patients who were in the nonactive phase of TED.81 The median

duration in the first Netherlands study was only slightly shorter at 13 and 14.5 months, for the treated, and the placebo groups, respectively.77 The median duration in the second Dutch study was 17 and 15 months, for the treated and the placebo groups, respectively. Subsequent to both the Mayo and the Dutch studies, a prospective study of 66 consecutive patients showed that disease activity could predict the response to treatment.82 In the patients with moderately severe Graves ophthalmopathy, euthyroid for 2 months preceding treatment with radiation therapy for either restriction of extraocular motility or proptosis >25 mm, response could be predicted on the basis of several features. A model to predict both response and outcome was developed from this analysis. Duration of ophthalmopathy >16 months had a 10 times lower probability of response to radiotherapy.82 Several studies have compared radiation dose and have also had conflicting results. Kahaly et al. compared 3 doses (10 and 20 Gy over 2 weeks and 20 Gy over 20 weeks) and concluded that a low-dose regimen of 20 Gy in 20 weekly fractions was more P.294

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P.297

P.298

P.299

P.300

P.301 effective and better tolerated. The evaluation of response was completed 4 weeks after the last treatment in the 20 Gy over 20 week group and 22 weeks after the last treatment in the 10 Gy and 20 Gy over 2 weeks groups, so the conclusions of this study are limited. A Japanese study of 31 patients concluded that 24 Gy of radiation was more effective than 10 Gy when combined with systemic corticosteroids.83 TABLE 15.1 Summary of Studies Comparing the Different Modalities of Treatment of Graves Ophthalmopathy Radiotherapy Author Study Treatment Conclusion/Limi (Date) Design/PurpoStudy Participants Protocol Outcome tations

Mourtis (2000)77

se Single-center, 60 outpatients with double-blind, moderately severe randomized, TED (30 assigned to placebo irradiation; 30 control trial assigned to sham irradiation)

To assess whether retrobulbar irradiation lessens severity of TED

Treatment Qualitative Study concludes group: 6 MV treatment that irradiation photon beam outcome: does not improve from Elekta Observed in outcome in terms SL 15 18/30 of reducing eyelid accelerator (20 irradiated retraction, Gy in 10 patients and swelling, or fractions over 9/29 sham proptosis; may be 12 d) patients (RR = some indication 1.9; 95% CI that irradiation 1.03.6, p = may improve 0.04). Motility motility improvement: Observed in 14/17 irradiated patients, 4/15 sham patients (RR = 3.1; 95% CI 1.37.4, p = 0.004) Diagnosed by the Placebo Eyelid following symptoms: Group: Same swelling: Eyelid retraction, protocol Observed in swelling, proptosis, without 4/11 irradiated impaired motility, irradiation; all patients, and including intraocular patients 5/12 sham pressure in upward examined 1 d patients (RR = gaze, including before and 4, 0.9; 95% CI intraocular fat 12, 24 wk after 0.32.4, p treatment by >099) the same Diplopia clinician improvement: (in extremes of gaze) observed in 9/12 irradiated patients, and 1/4 sham patient; (no diplopia) 2/5 irradiated, 1/11 sham patient Follow-up: No

Gorman (2001)78

significant difference between groups in terms of number of additional therapies needed (3 irradiated, 4 shamneede d no additional therapy); Orbital decompression 9 irradiated patients, 14 sham patients Single-center, 42 Graves patients Treatment: 6 Treated orbit atStudy unable to double-blind, with moderate TED MV photons 3 and 6mo: find a clinically or randomized, (one eye from each delivering 20 Muscle statistically placebo patient randomly Gy of external volume11 significant control trial allocated to receive beam mL (treated) difference irradiation, other eye irradiation at and 10.4 mL between treated sham irradiation) 10 fractions (untreated) and nontreated Diagnosed with the over 12 d, Proptosis21 orbit; therefore following symptoms: directed at one .8 mm concludes that +TSI level, orbit (initial (treated) vs. radiotherapy does euthyroid, eyelid treatment at 3 21.3 mm not improve edema, lid lag, lid mo and second (untreated) outcome in To evaluate retraction, bulging eye treated at 6 These were patients with efficacy of eyes, proptosis, mo); treated statistically but moderate TED irradiation restriction in major orbit compared not clinically therapy in muscle motion to untreated significantly TED orbit at 3, 6, different and 12 mo No other parameters were statistically significantly different; patients treated earlier in the course of the disease showed no

Gorman (2002)78a

Noncomparati 42 patients with ve moderate TED interventional (details described case series above) (follow-up period following RCT)

To evaluate long-term improvement (3 y) following orbital irradiation in moderate TED patients

difference in treatment outcome compared to patients with longer disease duration Same as above 3-y outcome: Uncontrolled Ancillary study failed to rehabilitation identify any procedures benefit to orbital orbital irradiation, and decompression suggests that (n = 8), orbital irradiation extraocular should no longer muscle surgery be considered a (n = 11), eyelidtreatment option surgery (n = for mild to 18) moderate TED Orbital changes in patients who were not surgically decompressed (n = 31)orbital fat increased from 12.114.0 cc (p <0.001) and muscle volume decreased from 10.78.4 cc (p <0.001); monocular range of motion showed no significant change, proptosis decreased 0.7 mm below the baseline and at 3 y (p = 0.01) Orbital

Gerling (2003)78b

Prummel (2004)79

changes in patients who were surgically decompressed (n = 7)orbit volume increased from 2734.6cc, proptosis decreased from 23.218.9 mm (p = 0.01) Multicenter, 97 Graves patients 6-MeV linear Appearance: Symmetrical blind, with active TED (43 accelerator; 8 Graded from differences found randomized irradiated with 2.4 fractions of 0.3 0100 p = with 2.4 and 16 study to Gy; 43 irradiated or 2.0 Gy over 0.42/0.09 Gy. Study compare with 16 Gy) 16 d two Hertel concludes that results of opposing measurements irradiation should irradiation asymmetrical for two eyes not exceed 2.4 with 2.4 fields added: p = Gy. Study did not Gyand 16 Gy 0.28 examine Eye effectiveness of movements: irradiation Vertical ductions measured on Goldmann added for two eyes p = 0.99 Muscle thickness: Mean of three cross-sectional areas of eight muscles on MRI, p = 0.26 Complaints: 0100 analog scale of five modalities, p = 0.19 Single-center, 88 Graves patients 5 MeV linear Clinical The study blind, euthyroid for 2 mo accelerator; measures: concludes that randomized with untreated mild treated in 10 23/44 orbital study to ophthalmopathy (44 divided responded in radiotherapy

compare irradiated and 44 irradiation to sham-irradiated no treatment. patients)

fractions over irradiated improves motility 2 wk. Patients group, 12/44 but had no examined at 3, sham group (p beneficial effect 6, and 12 mo. = 0.02). No on soft tissue All patients further involvement. The examined by treatment was quality of life same needed in scores improved ophthalmologi 15/44 of in a similar st for eyelid irradiated manner for both aperture, soft group and 7/44 groups and tissue of sham group observation was involvement, (p = 0.049) recommended as proptosis, Quality of life a good alternative motility, assessment: strategy. diplopia, and No difference visual acuity. was found Data from the (visual most affected function 8.2 in eye was treatment studied group vs. 10.5 in placebo group) Cost assessment: No difference in costs(5,007 in treatment group and 4,465 in placebo group)

Corticosteroids and orbital irradiation Marcocci Single blind, 82 Graves patients IVGC Proptosis: Study found that 64 (2001) randomized, with moderate to protocol: Significantly there is not much study severe cases of TED Methylprednis decreased in difference olone acetate IVGC group between IV and (15 mg/kg for from oral treatment of 4 cycles, 7.5 23.321.6 TED; however, mg/kg for 4 mm (p IV administration cycles) cycle = <0.0001), and seems to be better 2 infusions/2 ORGC group tolerated with less wk from side effects than 2321.7 mm the oral method (p <0.0001);

To evaluate the effect of oral glucocorticoid s (ORGC) vs. IVGC in association with orbital irradiation

final exophthalmom eter readings did not differ between groups(p = 0.41) ORGC Lid width: protocol: Width did not Prednisone differ between (100 mg/d for groups(p = 7 d, with 0.65) gradual weekly reduction until 25 mg dose is reached); then tapered to 5 mg/2 wk Duration of Diplopia: treatment = 22 Disappeared in wk 10/27 and did Radiotherapy: not change in 20 Gy 12/27 IVGC delivered to patients, each eye in 10 disappeared in fractionated 12/33 patients doses over 2 and did not wk change in Ocular 16/33 patients evaluation receiving carried out by ORGC; the same amelioration examiner rate did not significantly differ between the 2 treatment groups (chisquared = 0.06, p = 0.82) Overall clinical response: Statistical difference found in clinical

response to therapy between IVGC and ORGC groups (p = 0.02) Adverse effects: IVGC better tolerated than ORGC Bartalena Randomized 48 patients with Radiotherapy: Significant Study concludes 72 (1983) control trial active Graves 10 daily doses improvement that patients ophthalmopathy (24 of 2 Gy for 2 in both receiving patients with active wk groupspatie combined therapy TED randomly nts receiving showed a more treated with combination significant radiation/methylpred therapy or improvement in nisolone (12) or methylprednis clinical and methylprednisolone olone alone. ophthalmology alone (12), 24 indices. There additional patients was an inverse with active TED relationship submitted to between duration combined therapy); of patients were ophthalmopathy assessed in terms of and efficacy of ophthalmology index treatment, more and clinical favorable results observations when symptoms were of <2 y duration. To evaluate Methylprednis Ophthalmolog Major limitations the effect of olone: 7080y index: Mean to this study radiation in mg/d for 3 wk, final index design may limit combination gradually significantly the applicability with tapered by 5 reduced in of results, methylprednis mg weekly combination including one vs. until a daily group unbalanced methylprednis dose of 20 mg (decrease is treatment groups olone alone is reached; 4.8 in and differences in subsequently combination data collection reduced by group and 3.2 2.55 mg in every 23 methylprednis wks; olone group, p discontinued <0.005) after 56 mo

Marcocci (1991)73

Randomized 30 patients with Radiotherapy: Evaluation at Study concludes control trial to active TED (26 4 MeV linear 69 mo that combined evaluate the patients completed accelerator; 20 indicated that therapy produced effect of the study) 13 patients Gy delivered regression or more favorable radiation in group 1 received in 10 substantial results in terms of therapy combination therapy; fractionated improvement soft tissue combined 13 patients in group daily doses occurred in all changes and with 2 received radiation over 2 wk patients except extraocular corticosteroid alone one in group 1 muscle s vs. radiation and in only involvement therapy alone half in group 2 Prednisone: Mean Limitations: Study 100 mg/d Ophthalmolog size may limit the for 7 days, y Index was broad applicability of weekly significantly results reduction different to 25 mg between the was two groups (reached, 3.39 in group then 1 and -1.85 in tapered by group 2; p = 5 mg/d for 0.043); when 2 wk; evaluated Duration of clinically, the protocol study did not 56 wk find a statistical significance difference between groups (p = 0.23); adverse effects: Cushingoid features occurred in some cases during combined therapy because of corticosteroid s Prummel Randomized 56 patients with Radiation No specs class: Study concludes (1993)71 double-blind moderate to severe group: 5 MeV 13/28 radiation there is a similar study to Graves linear patients response rate to

compare the ophthalmopathy (28 accelerator; tenimproved; efficacy of patients received oral 2 Gy doses 14/28 radiation with prednisone and sham over 2 wk prednisone that of oral radiation; 28 patients prednisone received radiation improved and placebo capsules) Medication Monocular group: Pred eye nisone 60 movements: mg for 2 8/28 radiation wk, 40 mg improved, for 2 wk, 7/28 30 mg for 4 prednisone wk, 20 mg patients for 4 wk, improved tapered by 25 mg per wk. Patients examined 0, 4, 12, and 24 wk after treatment by the same ophthalmol ogist RCT, randomized controlled trial; TED, thyroid eye disease.

radiation and prednisone after 24 wks. Both treatments had minimal effect on proptosis. Seventy-one percent of prednisone group had moderate or severe side effects and study concluded that radiotherapy should replace prednisone treatment. The study was limited by inadequate follow-up time to detect the side effects of radiation

Figure 15.4 Thirty-two-year-old woman with proptosis and lid retraction who underwent subcaruncular medial wall and swinging eyelid floor decompression followed by correction of upper lid retraction. Deleterious effects from radiation are often not realized until long after the treatment. Long-term follow-up of 250 patients irradiated for progressive Graves ophthalmopathy failed to show a difference in radiation-induced cancer death but did not have sufficient numbers to determine a

difference.84 A second long-term follow-up study also failed to show a difference in mortality in 245 patients but did show a significant risk of retinopathy (p = 0.0002).85 Lifetime risk of radiation-induced cancer is dependent on the age and the dose of radiation.86 The calculated risk of radiation-induced cancer after retrobulbar irradiation for Graves ophthalmopathy is 1.2%.87 Surgical Treatment Orbital, strabismus, and lid surgery are most commonly performed as part of the rehabilitative phase of TED treatment (see Fig. 15.4). A randomized trial of 15 patients with very active Graves ophthalmopathy and optic neuropathy compared surgical decompression to steroid treatment. Immediate surgery did not result in a better outcome.74 Most of the studies summarized in Table 15.1 show that radiation and immunosuppression do not change proptosis. Decompression surgery has been shown to reduce proptosis.88,89 A quality of life survey showed a significant correlation between improvement in proptosis and quality of life (p = 0.05).90 Conclusions Active phase thyroid disease improves naturally in many patients. The literature on the therapy for Graves ophthalmopathy consists largely of single-center RCTs, retrospective case series, and prospective cohort studies. Most randomized controlled studies indicate that radiation does not provide any clinically or statistically significant improvement in the outcomes over placebo or steroids. Radiation has been associated with retinopathy, particularly in diabetic patients. Radiation may also be associated with a higher lifetime risk of cancer. The dose of steroids needed for immunosuppression of active phase disease is associated with side effects in most patients. These side effects range from weight gain to liver failure. Neither steroids nor radiation reduce the need for decompression or rehabilitative surgery. Current cigarette smoking is strongly associated with prevalence of Graves ophthalmopathy and the level of cigarette use correlates with the severity of eye disease. Decompression surgery correlates with improvement in quality of life metrics. The benefits of active phase treatment must be weighed against the risks. The disease duration has been shown to predict response to immunosuppressive therapy; the failure to show a benefit of radiation could be secondary to inclusion of patients in later phases of the disease process. An evidence-based benefit has not been shown with radiation, and given that there is a known risk of retinopathy and a theoretical risk of cancer, radiation should only be considered in older patients who are also at low risk for retinopathy. Concurrent steroid treatment may improve the outcome. High P.302 dose steroids should only be used when the pathology and treatment benefit outweigh the risks of the side effects. Liver function needs to be monitored during steroid treatment.

15.4 Orbital Involvement in Autoimmune Disorders: Graves Disease

Definition Autoimmune disorder with orbital involvement frequently associated with thyroid dysfunction. Histologic examination reveals inflammatory infiltration of the orbital cavity. Epidemiology: Women are affected eight times as often as men. Sixty per cent of all patients have hyperthyroidism. Ten per cent of patients with thyroid disorders develop Graves disease during the course of their life. Graves disease is the most frequent cause of both unilateral and bilateral exophthalmos. Etiology: The precise etiology of this autoimmune disorder is not clear.Histologic

examination reveals lymphocytic infiltration of the orbital cavity. The ocular muscles are particularly severely affected. Fibrosis develops after the acute phase. An autonomous adenoma of the thyroid gland is not associated with Graves disease. Some patients with Graves disease never exhibit any thyroid dysfunction during their entire life. Symptoms: The onset of this generally painless disorder is usually between the ages of 20 and 45. Patients complain of reddened dry eyes with a sensation of pressure (symptoms of keratoconjunctivitis sicca) and of cosmetic problems. Ocularmotility is also limited, and patientsmay experience double vision. Diagnostic considerations: Cardinal symptoms include exophthalmos, which is unilateral in only 10% of all cases, and eyelid changes that involve development of a characteristic eyelid sign (Table 15.3 and Fig. 15.3). Thickening of the muscles (primarily the rectus inferior and medialis) and subsequent fibrosis lead to limited motility and double vision. Elevation is impaired; this can lead to false high values when measuring intraocular pressure with the gaze elevated. 15.4 Autoimmune Disorders and the Orbit: Graves Disease
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Table 15.3 Eyelid signs in Graves disease Eyelid sign Explanation ! Dalrymples sign Upper eyelid is retracted with visible sclera superior to the limbus and widened palpebral fissure with developing exposure keratitis (overactive muscle of Mller). ! von Graefes sign Upper eyelid retracts when the eye depresses (overactive muscle of Mller). ! Giffords sign Upper eyelid is difficult to evert (due to eyelid edema). ! Stellwags sign Rare blinking. ! Kochers sign Fixed gaze. ! Eyelid flutters when closed Patient with Graves disease, more severe in the left than in the right eye. Fig. 15.3 Typical signs include exophthalmos, which here is readily apparent in the left eye, retraction of the upper eyelid with visible sclera superior to the limbus (Dalrymples sign), conjunctival injection, and fixed gaze (Kochers sign).

The tentative clinical diagnosis of Graves disease is supported by thickening of the extraocular muscles identified in ultrasound or CT studies (Fig. 15.4). The further diagnostic work-up requires the cooperation of an internist, endocrinologist, and radiologist. 15 Orbital Cavity
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CT image of a patient with Graves disease. Fig. 15.4 The image shows obvious thickening of the extraocular muscles in the right orbit, primarily the rectus medialis (1) and rectus lateralis (2), and of the rectus medialis (3) in the left orbit.

Differential diagnosis: Rarer clinical syndromes such as orbital tumors and

orbital pseudotumors must be excluded. Treatment: The main principles in treating the disease in its acute stage include management of the thyroid dysfunction, systemic cortisone (initially 60100mg of prednisone) and radiation therapy of the orbital cavity . Surgical decompression of the orbital cavity is indicated in recurrent cases that do not respond to treatment to avoid compressive optic neuropathy. Exposure keratitis (keratitis due to inability to close the eye) should be treated with artificial tears or tarsorrhaphy (partial or complete suture closure of the upper and lower eyelid to shorten or close the palpebral fissure). In the postinflammatory stage of the disease, eye muscle surgery may be performed to correct strabismus. Clinical course and prognosis: Visual acuity will remain good if treatment is initiated promptly. In the postinflammatory phase, exophthalmos often persists despite the fact that the underlying disorder is well controlled

Orbital anatomy
The bony orbit has four margins and walls and is adjacent to the ethmoid sinus (medial) and maxillary sinus (inferior). It contains the optic foramen for the optic nerve and ophthalmic artery, the superior orbital fissure (cranial nerves and blood vessels) and inferior orbital fissure.The infraorbital nerve lies in the floor, partly in a bony canal.The orbit contains a lot of fat and connective tissue septae that support and cushion the eye and its muscles, optic nerve, nerves and blood vessels.

Orbital assessment
History
Gradual or sudden onset. If slow/non-inflamed it is more likely to be benign. Unilateral or bilateral. Orbital swelling/sunken. Orbital pain. Periorbital redness (e.g. orbital cellulitis). Periorbital numbness. Visual disturbance. Double vision. Drooping eyelid. Systemic: malignancy or thyroid problem. Previous trauma. Ascultation for a bruitcaroticocavernous fistula.

Clinical examination Visual function (if eye present) and eye examination
Visual acuity and pupil reactions. Colour vision visual fields. Retina and optic disc.

Globe position
Measure proptosis with Hertel exophthalmometryis it axial or non-axial? Basic orbital assessment 61 Enophthalmos. Is there a history of trauma and possible orbital floor fracture? Is there a phthisical eye? Is there an ocular prosthesis? Has the patient had an eye enucleated? Was there an orbital implant placed after enucleation/evisceration? Is there a secondary post-enucleation socket syndrome? Are the eye movements restricted? Is the socket lining contracted?

Check cranial nerve (CN) function

IIIrd, IVth and VIth CN: extraocular muscle movement. VIIth CN: upper facial musculature. Vth CN: corneal, periorbital and forehead sensation.

Feel the orbit

Palpate the orbital rim. If a mass is detected, is it separate from the rim? Describe its feel and shape and draw a picture of its shape and location.

Complete the examination

Palpate the temporal fossa for extension of swelling. Exclude pre-auricular, submandibular and cervical lymphadenopathy. Examine the neck for thyroid enlargement or thyroid scar. Check sensation in skin around orbit.
Proptosis Axial (anteroposterior protruding globe) without horizontal or vertical displacement. This suggests a generalized orbitopathy such as thyroid eye disease or an intraconal mass. Non-axial. Horizontal or vertical displacement of globe caused by a mass pushing it sideways. For instance, a lacrimal gland tumour in the superolateral quadrant pushes the globe inferomedially. WARNING Orbital tumour spread. The orbit does not have lymphatics, but extensive tumour that involves the lids and periorbital area can metastasize to local lymph nodes.

Investigations
CT scanning. Axial and coronal views show the position of the optic nerve well and also the sinuses and orbital walls (request bone window settings too). Suspected vascular lesions need contrast. MRI. Good for soft tissue but does not show bone so well. Orbital ultrasound. Colour Doppler ultrasound to measure size and show bloodflow/velocity within lesion.
KEY POINTS Proptosis is axial or non-axial. Palpate the orbit to help detect a mass.

62 Sub-specialtyEyelid, lacrimal and orbit

28 Orbital and thyroid eye disease

Marked proptosis and redness active phase Graves orbitopathy (thyroid eye disease) Wearing a thick artificial eye but still very enophthalmic Post-enucleation socket syndrome no orbital implant placed at time of enucleation Thick artificial eye Porous polyethylene sphere implant inserted into socket. Orbital sphere implant is needed to replace lost volume Enucleation Bilateral proptosis, periorbital swelling and left esotropia quiet phase CT scan enlarged medial and inferior rectus muscles in Graves orbitopathy Tumour behind eye Right proptosis from large cavernous haemangioma CT scan showing tumour (benign) Indications for enucleation include a painful blind eye, choroidal malignant melanoma and a severely disrupted eye following trauma. The eye is eviscerated if there is an intractable endophthalmitis

Aims
1 Management of Graves orbitopathy. 2 Recognize an artificial eye. This chapter cover proptosis, orbital masses and enucleation.

Common orbital problems

Adult: Graves orbitopathy (thyroid eye disease) (most common); idiopathic orbital inflammation; cavernous haemangioma; lacrimal gland tumour; secondary tumours;

nerve cell or sheath tumours. Child: dermoid cyst; haemangioma; rhabdomyosarcoma; Craniofacial abnormality.

Graves orbitopathy
Most patients present within the first 612 months of hyperthyroidism. Male patients and smokers have a more aggressive disease. There is an active phase with inflammation which lasts up to 1 year, and a subsequent inactive stable phase.The former is treated medically with immunosuppression (e.g. steroids and azathioprine) and once the disease is inactive surgery to the orbit,muscles and eyelids can be considered.
WARNING Early orbital decompression surgery is only done if there is marked compressive optic neuropathy.

There is a varied presentation: Proptosis. Reduced colour vision from optic nerve compression. Restrictive strabismus with mainly inferior and/or medial rectus muscle enlargement causing diplopia. Eyelid retraction. Lagophthalmos. Exposure keratitis. Conjunctival redness and cheimosis. Periorbital swelling. The aim of treatment is to preserve vision, with eyes comfortable and looking normal, with full lid closure.
Graves orbitopathy management Indication Phase Medical treatment Surgery Compressive Active Pulsed steroid Orbital optic therapy decompression neuropathy Systemic steroids, azathioprine and orbital radiotherapy Proptosis Inactive Orbital decompression Strabismus Inactive Adjustable suture rectus recession Eyelid Inactive Graduated retraction retractor recession (upper eyelids) Hard palate mucosal graft, alloderm or auricular cartilage (lower eyelids) Periorbital Inactive Blepharoplasty swelling Skin changes Inactive Laser resurfacing skin

Orbital and thyroid eye disease 63

Orbital and lacrimal gland tumours

Orbital and lacrimal gland tumours cause proptosis and require incisional or excisional biopsy by a trained oculoplastics orbital surgeon. Lymphoma and metastases are the commonest malignant tumours. Many anterior and mid orbital tumours can be biopsied via a skin approach. More posterior intraconal and lacrimal gland tumours (pleomorphic adenoma) require excision via a lateral orbitotomy.

Enucleation

When an eye is removed its volume must be replaced by a buried spherical orbital implant to which the rectus muscles are attached. An ocular prosthesis (artificial eye) is made to match the normal eye; usually it is acrylic and hand painted. If the volume of the enucleated eye is not replaced the patient has a sunken socket appearance called post-enucleation socket syndrome and may need a secondary buried orbital implant.
KEY POINTS Graves orbitopathydo decompression before eyelid surgery. Important to replace eye volume lost at enucleation/evisceration with an orbital implant and artificial eye.

Thyroid-Related Ophthalmopathy Thyroid-related ophthalmopathy is an immune-mediated process that results in orbital inflammation and scarring. It occurs four to five times more commonly in women than men and is most common in middle age. The results may be mild swelling of the orbit, or it can result in severe proptosis, lid retraction, corneal exposure, motility disturbances, or visual loss secondary to optic nerve compression. Ninety percent of patients have or have had a systemic thyroid abnormality. Clinical Features Thyroid-related ophthalmopathy is characterized by chronic orbital inflammation and scarring. Usually, this is a bilateral process, but it can be asymmetric. This autoimmune process results in infiltration of extraocular muscles and orbital fat by inflammatory cells in the short term and by mucopolysaccharide and collagen in the long term. The disease process is marked by early inflammation and long-term fibrosis and scarring. Early manifestations of the disease can often be subtle, with nonspecific redness, irritation, chemosis, and eyelid swelling. The presence of a systemic thyroid imbalance is helpful in establishing the diagnosis but not necessary to make the diagnosis, because 10% of the patients are euthyroid. Early signs of lid retraction, lid lag, or evidence of any systemic thyroid imbalance help confirm the diagnosis. As the disease process progresses, eyelid retraction and lid lag become more obvious, and corneal exposure must be watched for. Proptosis and restriction of motility are also later signs (Fig. 10.124). The inferior rectus muscle is the most commonly involved muscle, followed by the medial rectus, making restricted upgaze and lateral gaze the most common motility disturbances. The CT scan shows involvement of the muscle bellies and sparing of the tendons (Fig. 10.125). If extraocular muscle involvement progresses, the optic nerve may become compressed at the orbital apex by these swollen muscles. Visual acuity, color vision, visual fields, and presence of an afferent pupillary defect must all be monitored in these patients to rule out optic nerve compression. Figure 10.125. Axial (A) and coronal (B) computed tomography scans show enlargement of all extraocular muscles in a patient with thyroid-related ophthalmopathy. A patient typically goes through a period of 6 to 24 months of active disease. During this period, there is active inflammation, and the ocular manifestations are changing. After this phase is completed, the eye typically remains stable, despite the residual scarring of the muscles and orbit. Management Management of thyroid-related ophthalmology is complicated by the wide variability of disease manifestations and by a lack of consensus about the best treatment. Initial assessment of the patient requires determination of disease activity, which is important in making decisions about management. All patients require an evaluation and monitoring of their thyroid status. Patients

may be euthyroid on presentation, but their thyroid status must be followed over time. Careful evaluation for optic nerve compression or significant corneal exposure must be done. All patients will benefit from lubrication of the eyes. Good patient education about thyroid-related ophthalmopathy and what the patient can expect is invaluable. Patients with active disease are candidates for orbital irradiation. Irradiation appears to stop progression of thyroid-related ophthalmopathy in a significant percentage of patients. Irradiation does not reverse the scarring already present from the disease. Irradiation takes up to 6 months to have full effect, so any acute problem such as optic nerve compression needs to be treated with other modalities, often in conjunction with irradiation. Patients with active disease P.419 will require an orbital CT scan. This helps assess muscle size, activity, and may later assess response. Patients with inactive disease are without active inflammation and are unlikely to benefit from irradiation. Treatment includes observation, lubrication, and possible surgery to correct changes caused by thyroid-related ophthalmopathy. These patients do not require imaging unless the diagnosis is in question or decompressive surgery is being considered. Systemic steroids are indicated for short-term management of the inflammation from thyroidrelated ophthalmopathy. The exact mechanism of action is unclear but steroids are effective in decreasing inflammation. This is especially helpful in optic nerve compression or severe corneal exposure. Irradiation itself takes weeks to work, so the addition of steroids gives rapid, shortterm treatment. Long-term use of steroids is limited by side effects. Surgical management, which often involves multiple stages and treatments over months to years, may include orbital decompression, eye muscle surgery, and eyelid surgery. The need for acute surgical management of severe disease has decreased with the use of irradiation. There still are the rare patients who will require acute orbital decompression for optic nerve compression. More often, surgery is required to try and reverse the results of the chronic orbital scarring form thyroid-related ophthalmology.

Thyroid eye disease (TED)

Other names: dysthyroid eye disease, endocrine exophthalmos, Graves dysthyroid ophthalmopathy, thyroid related orbitopathy. TED is the most common cause of unilateral and bilateral exophthalmos in adults. Although often referred to as an eye disease, ocular and optic nerve involvement is secondary to inflammatory enlargement of extraocular muscle and subsequent scarring.

Clinical presentation
The disease has acute and chronic stages and there is marked variation in severity ranging from conjunctival congestion to severe proptosis with secondary exposure keratitis. The acute stage of TED occurs on average 2.5 years following the diagnosis of systemic or localised thyroid disease, although diagnosis of TED does not rely on a prior history of thyroid disease. The stage of disease does not correlate with thyroid function tests.

Diagnosis
One of the more popular methods for describing the clinical features of this disease is to use Werners NOSPECS mnemonic:

 No signs or symptoms. Only upper lid signs: retraction, lag, and stare. Soft tissue: resistance to retropulsion, oedema of conjunctiva, caruncle and eyelids, lacrimal gland enlargement, and injection over rectus muscle insertions. Proptosis. Extraocular muscle involvement (motility disorders). Corneal involvement (exposure). Sight loss due to optic nerve compression. The mnemonic does not necessarily represent a stepwise progression of TED. The diagnosis of TED relies on accurate CT/MRI orbital imaging. The characteristic finding is the enlargement of the rectus muscles with sparing of the tendinous insertions. The important differential diagnoses to consider are: orbital lymphomas and idiopathic orbital inflammatory disease. A biopsy is rarely indicated (see below).

Pathogenesis
Both humoral and cell mediated immunity mechanisms have been implicated, but, as yet, the specific abnormalities have not been identified. As a result of accumulations of T cells and B cells within the muscle, there is an excessive mucopolysaccharide deposition which attracts fluid with resultant swelling. Chronic inflammation is then followed by fibrosis.

Genetics
Women are 310 times (according to different authors) more likely to be affected by TED (mean age of onset is 41 years). The condition occurs at a later age in men (later than 50 years), but is more severe.

Possible modes of treatment

Treatment for TED is controversial. Topical lubricants are used to treat exposure symptoms. Systemic steroids and low dose radiotherapy can control the acute disease. Orbital decompression may be carried out if there is severe proptosis which is refractory to medical treatment. In chronic disease, when there is a greater problem with orbital fibrosis, treatment includes eyelid surgery (lid lowering) and strabismus surgery for diplopia.

Macroscopic
Due to advances in orbital imaging technology, tissue biopsy for the diagnosis of TED is rare and unnecessary. However, specimens are occasionally encountered in autopsy material (Figure 5.20) which reveals thickened and pale extraocular muscles with sparing of the tendinous insertions. Glaucoma, compressive optic atrophy, and exposure keratopathy may be evident due to uncontrolled proptosis.

Microscopic
The individual extraocular muscle fibres are separated initially by mucopolysaccharide accumulation and infiltration by lymphocytes and plasma cells (Figure 5.21). This is followed by fibrous tissue replacement (Figure 5.22). The orbital fat is of normal appearance.