Etiology

Endocrine orbitopathy (EO) is the most common extrathyroidal manifestation of Graves’s disease and/or autoimmune thyroid disease. The EO can occur before, during, or after the onset of the thyroid disease. ¹ The eyes are usually affected asymmetrically. Although women are affected more frequently by EO, men are often confronted with a particularly difficult progression of the disease. ² The general manifestation age lies between 40 and 50 years. The EO typically occurs combined with Graves’s disease and positive TSH (thyroid stimulating hormone) receptor antibodies. It occurs only rarely with Hashimoto’s thyroiditis with antibodies against thyroperoxidase or thyroglobulin instead, or (even less commonly) with no autoimmune thyroid disease present. Of the 250 EO patients who were studied prospectively at the Johannes Gutenberg University orbital center in Mainz, Germany, 231 (92.4%) had Graves’ disease, 12 (4.8%) had Hashimoto’s thyroiditis, and 7 (2.8%) had no autoimmune thyroid disease. ³ The prevalence of EO in the general population is estimated to be 16 women and 3 men per 100,000 per year. ⁴ A clinically relevant progression of the EO can be observed in about one-fourth of all patients with Graves’s disease. If one includes palpebral changes as well, the number increases to 40%. Using computer tomography or magnetic resonance imaging, or by measuring the intraocular pressure, subclinical abnormalities were revealed in most patients with Graves’s disease. Nevertheless, severe forms of EO are observed in only 3 to 5% of all cases. ^{5,​ 6}

7.1.2 Pathogenesis

Immune Pathogenesis of Orbital Changes

The immune process in the orbital space is composed of inflammatory reactions, the proliferation of connective and adipose tissue (both around the outer eye muscles as well as within the perimysium and endomysium), and finally an excessive production of glycosaminoglycans from orbital fibroblasts. The inflammatory reaction is mainly characterized by an infiltration of T lymphocytes (CD4⁺, CD8⁺, CD45RO⁺, CD45RB⁺) in particular, whereby plasma cells and macrophages are increased. ⁷ The proliferation of lymphocytes, plasma cells, and macrophages leads to a stimulation of the orbital fibroblasts, and to a massive production of collagen and mucopolysaccharides. The orbital fibroblasts are uniquely sensitive to certain cytokines, which explains the anatomical localization of the immune response. The fibroblasts release proinflammatory cytokines (especially interleukins IL-6 and IL-8) and thus stimulate the nuclear factor κB. ⁸

The volume of the eye muscles can increase up to 2 to 3 times its usual size. Most commonly affected are the inferior and medial rectus muscles. It has been shown in animal models that a secondary effect is the obstruction of orbital veins, depending on the respective anatomical circumstances. This results in additional edema formation and amplification of the inflammatory response. ⁹ A part of the orbital fibroblasts are so-called preadipocytes that can be converted into fat cells, as observed in vitro. ¹⁰ During this conversion, the preadipocytes increasingly express the TSH receptor, supporting the theory that this receptor is an important autoantigen in the orbital immune response.

There are hints that T lymphocytes with similar molecular T-cell receptor repertoires can migrate into both the thyroid tissue and the orbital tissue, which suggests antigen similarities of both tissue types. ^{11,​ 12} Both the TSH receptor as well as a TSH receptor variant have been detected in orbital connective and adipose tissue at RNA and protein levels. Since the cloning of the TSH receptor, there are numerous indications for its extrathyroidal and orbital presence. ^{13,​ 14,​ 15,​ 16,​ 17,​ 18} The extracellular portions of the TSH receptor thus come into consideration as cross-reacting antigenic determinants for T lymphocytes and as a target structure for EO patients. This perception is supported by the fact that in animal experiments the injection of TSH receptors triggers both Graves’s disease and characteristics of EO. However, a functional TSH receptor or other thyroid antigens have not yet been detected in orbital tissue. ^{19,​ 20} Investigations revealed that there is in fact a link between the activity and severity of the EO and the height of the measured TSH receptor antibody titers. ²¹ On the other hand, there are also indications regarding other orbital proteins with which the immune system reacts. ²² Orbital T cells react with the patient’s own orbital protein fragments, although lymphocytes should be tolerant against autologous tissues. ²³ Hence, the characterization of these antigenic structures is likely to bring further enlightenment regarding the pathogenetic backgrounds of the EO.

After the acute process including lymphocytic infiltration of the orbital tissue and the activation of fibroblasts, there follows a chronic stage. The histopathological correlate is an increasing fibrosis. Consequently, the transformation and proliferation of the tissue within the—anatomically rather narrow—orbital space leads to a pressure increase, which causes the characteristic symptoms of the EO ( ▶ Fig. 7.1).

Pretibial Myxedema and Acropachy

The EO is not only closely related to autoimmune-determined thyroid disorders; it is part of a complex disease pattern that can affect several organs. Besides the thyroid and eye manifestations in the progression of autoimmune hyperthyroidism, it may, for example, come to changes in the morphology and functioning of the heart. ²⁴ About 5% of patients suffering from Graves’s disease and EO also show a peculiar gelatinous inflammatory swelling in the area of the lower leg and forefoot (pretibial myxedema), as well as alterations in their fingers and toes (acropachy). Patients with an endocrine dermopathy regularly show EO and high titers of TSH receptor antibodies. As in the thyroid and orbital tissue of patients suffering from Graves’s disease, specialized T lymphocytes can also be detected in the actively inflamed pretibial myxedema tissue. The accumulation of glycosaminoglycans and other dermal connective tissue components in the dermal subcutis due to the cytokine-based stimulation of pretibial fibroblasts is the morphological correlate of nodular or diffuse pachyderma related to the pretibial myxedema ( ▶ Fig. 7.2).

Risk Factors

Patients should refrain from smoking and avoid psychological stress, as, according to the evidence, both are modifiable risk factors that amplify the autoimmune process. ²⁵ Studies have shown that patients suffering from Graves’s disease developed EO significantly more often when smoking. ²⁶ It was also revealed that nicotine negatively affects therapeutic success regarding radioactive iodine therapy, ²⁷ steroid therapy, and retrobulbar radiotherapy. ²⁸ The phenotype and function of peripheral T lymphocytes are also affected by smoking, and the production of acute-phase proteins, complement factors, and interleukin-1 is enhanced. ²⁹ It is also known that emotionally stressful incidents favor the occurrence of autoimmune hyperthyroidism, ³⁰ and that chronic psychological stress as well as genetic predisposition influence antithyroid therapy negatively. ^{31,​ 32}

7.2 Clinical and Laboratory Investigations

George J. Kahaly

7.2.1 Clinical Investigations

Patients suffering from EO usually report slowly increasing local discomfort that is more pronounced in the morning than in the evening. ³³ Usually, the focus is on eyelid reactions; other symptoms such as periorbital edema, pain and pressure behind the eyes, photosensitivity, foreign body sensation, lacrimation, and exophthalmos come in varying degrees of severity and frequency ( ▶ Table 7.1). Severe conjunctivitis, local infections, and corneal defects are possible results of an incomplete eyelid closure. The eye muscle changes result in motility disorders of the eye, with consequent diplopia. A severe complication is pinching of the optic nerve, which may result in the loss of visual acuity and visual field failures or even complete blindness. ^{2,​ 6}

In a study on the natural disease progression in 59 patients with EO, the symptomatology improved in 65% spontaneously; in 22% it remained unchanged; and only 13% of patients showed deterioration. ³⁴ Activations are described in connection with a recurrence of the underlying thyroid disease or after surgical orbital decompression operations. ³⁵ In about half of the patients, the measurement of TSH receptor antibody titers allowed an estimation of the severity and course of the EO. ³⁶

In principle, all eye sections should be examined ophthalmologically. The degree of the exophthalmos is determined and quantified by measuring the sagittal distance between the corneal apex and the lateral osseous orbital rim (Hertel exophthalmometer). Examination of the motility of the extraocular muscles and the resulting diplopia is important for potential surgery later. Pathological pupillary responses, visual field defects, and disturbed color vision are early signs of optic nerve compression that may be detected by an ophthalmologist even before a reduction of central vision acuity occurs ( ▶ Table 7.2). From visual evoked potentials, early stages of optic nerve dysfunction may also be revealed before the decrease of visual acuity. ³⁷

The changes within the eye socket are dynamic processes that cannot be described according to a regular scheme. For an accurate assessment of the disease’s progression, the activity and severity of the EO are evaluated using established scores.

The activity of the EO can be classified based on a 7-point scale ( ▶ Fig. 7.3; ▶ Table 7.3). It is considered to be clinically active when inflammatory processes with edematous swelling, disruption of the venous outflow, and thickening of the affected muscles dominate ( ▶ Fig. 7.4). Patients complain about bulging eyes, burning, foreign body sensation, and peribulbar pressure pain. These symptoms can be intensified when moving. Eyelids, conjunctiva, and lacrimal caruncle may be swollen and/or red.

The severity of the EO is classified based on a 6-class scheme ³⁸ ( ▶ Fig. 7.5; ▶ Table 7.4). Principally, the disease is considered to be severe if a corneal injury or optic nerve compression is present. To date, the evidence-based recommendations of the European interdisciplinary working group (European Group on Graves’s orbitopathy = EUGOGO) for the management of EO ^{39,​ 40} distinguish the following severity classifications.

• 
  

  Mild EO: in patients whose daily lives are only insignificantly affected by the signs and symptoms of the EO, so that neither immunosuppressive nor surgical therapy is appropriate. These patients usually show one or several of the following symptoms: minor eyelid retraction (≤2 mm), mild soft tissue involvement, exophthalmos ≤ 3 mm above the standard value according to age and race, temporary or missing diplopia, corneal inflammation, which responds to a local treatment with a tear replacement solution.

  
  
• 
  

  Moderate to severe EO: in patients without impairment of eyesight, yet whose daily lives are affected by the symptoms of the disease, justifying immunosuppressive (with active EO) or surgical (with inactive EO) therapy. Patients of this category usually suffer from one or more of the following symptoms: eyelid retraction ≥ 2 mm; moderate to severe soft tissue involvement; exophthalmos ≥3 mm above the standard value according to age and race; inconstant or constant diplopia.

  
  
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  Eyesight endangering EO: patients with optic neuropathy and/or corneal decompensation. This category requires immediate intervention.

  
  
  
  

  

  
  

  Fig. 7.5 (a) Mild endocrine orbitopathy. Eyelid swelling, slight upper lid retraction on the right eye, only mild exophthalmos. According to the light reflex nearly physiological eye bulb position (at least in the primary position). (b) Severe endocrine orbitopathy. The significant eyelid symptoms along with the strabismus indicate a serious disease. An optic nerve compression occurred additionally in this case which is not visible in this photograph.

  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  

  Table 7.4 EO severity classification

  Class	Criterion	Elaboration
  1	Clinical signs of EO	For example: eye lid reactions
  2	Degree of inflammation/soft tissue involvement	For example: corneal reddening and swelling
  3	Exophthalmos	Using the Hertel exophthalmometer
  4	Eye bulb motility disorders	For example: diplopia/strabismus
  5	Corneal involvement	For example: superficial punctate keratopathy or corneal ulceration
  6	Optic nerve involvement	Loss of visual acuity/neuropathy

7.2.2 Laboratory Examinations and Medical Imaging

The EO usually manifests in close temporal relation (6–12 months) to hyperthyroidism. ²⁵ The procedure along a standardized diagnostic staging system has been proven effective ⁴¹ and also allows for evaluation of the progression of the disease. The primary task is clinical and laboratory control of the thyroid function including the determination of basal serum values for TSH, free T₄ and free T₃. ⁴² The presence of thyroidal antibodies (specific TSH receptor, thyroid peroxidase, and thyroglobulin antibodies) facilitates the attribution of the thyroid dysfunction to Graves’s disease in the case of clinically inconclusive findings. The thyroid examination is completed by ultrasonography of the thyroid gland and possibly scintigraphy. The quite typical ultrasound image of Graves’ disease shows a diffuse goiter with hypoechoic, fanned pattern, as well as a significantly increased vascularization of the enlarged organ. A scintigram usually depicts the thyroid as diffusely retentive. In patients suffering from Hashimoto’s thyroiditis the thyroid is depicted as an extensive or circumscribed hypoechoic region.

Medical imaging techniques regarding the orbit (CT and/or MRI) are only applicable preoperatively and are used in unclear or unilateral cases. ^{43,​ 44,​ 45} In this regard, ocular myositis or idiopathic orbital inflammation is the most common differential diagnosis of EO. ⁴⁶

7.2.3 Clinical Recommendations for Practical Use

Patients suffering from EO in an acute stage should be monitored closely and in an interdisciplinary fashion in order to detect possible impairment of visual acuity, vision field defects, or corneal lesions at an early stage. Semiannual control examinations are recommended, even after reaching a stable euthyroid condition. ⁴⁷ In analogy to the relapse predictions regarding hyperthyroidism during Graves’s disease, TSH receptor antibody determination can also predict aggravation of EO in patients with high antibody levels. This information may influence treatment decisions, though these should be taken only by experienced specialists. The therapy can only be considered optimal if carried out as an interdisciplinary collaboration, involving experts working together in coordination. With the establishment of specialized orbital centers and a correspondingly consistent exploration of influencing factors and pathophysiological relations as well as of genetic factors, a better targeted therapy of the EO will be available, including, for example, improvement of the quality of life, which is significantly negatively affected. ⁴⁸ Ideally, this objective will be reached by the founding of specialized orbital centers. ⁴⁹ The Department of Medicine of the Johannes Gutenberg University Medical Center in Mainz, Germany, for example, offers a weekly multidisciplinary consultation period conducted by endocrinologists and relevant experts from the eye, ENT, radiotherapy, and psychosomatic clinics as an inherent part of its patient care.

7.3 Ophthalmological Findings and Complications

M. A. Varde and B. Wiechens

EO is an autoimmune disorder affecting the orbital tissues and leading to characteristic changes observable in clinical examination. Complications can lead to irreversible visual loss in case of corneal or optic nerve involvement. Changes in the appearance can cause psychological problems for patients and lead to depression.

7.3.1 Classification of Findings

Signs of periocular inflammation characterize the active stage of EO. The Clinical Activity Score (CAS) is used to assess the activity of the disease. The CAS is regarded the best predictive factor for the progression of EO and is therefore important for the planning of anti-inflammatory treatment strategies such as steroid therapy, immunosuppressive therapy, or radiotherapy. ⁵⁰ The CAS is based on clinical signs and does not require imaging ( ▶ Table 7.5). It is important to ensure that the findings are actually caused by active inflammation. Symptoms of dry eye, a common condition in EO, may also cause pain, variations in visual acuity, and conjunctival redness, while chemosis in relation to itching can be caused by an allergic reaction.

The severity of the disease is evaluated using the NOSPECS Score ( ▶ Table 7.6). This score is also elicited in each consultation in order to assess the progression of EO and to decide on potential interventions. A disadvantage of the score is the fact that it implies a chronological progression from Stage 0 to Stage VI that does not necessarily occur in each individual case. For example, a compressive optic neuropathy is often associated with only slight exophthalmos and no corneal involvement.

A more recent classification is the LEMO, which takes into account the independence of signs and symptoms that occur as well as their severity.

Important clinical signs, symptoms, and complications of EO will subsequently be discussed in more detail.

7.3.2 Dry Eye Syndrome

Dry eyes are not only a very common problem in otherwise healthy people but are also frequently found in EO and other autoimmune diseases. In general, two main causes of dry eyes can be differentiated: increased evaporation and hyposecretion. The components of the tear film are discussed in more detail in Chapter ▶ 15.1. Hyposecretion of tears is caused by direct lymphocytic infiltration of the lacrimal gland as well as being due to the effect of TSH receptor autoantibodies. Lid retraction, lagophthalmos and a decreased blink rate (as discussed below) result in increased evaporation of tears. The meibomian gland function is also affected by thyroid hormones. Even therapeutic measures for EO can lead to dry eyes: Hypothyroidism (e.g., after thyroablative treatment), irradiation of the orbit, and various surgical interventions in the lid area (ptosis surgery, blepharoplasty) are associated with dry eye syndrome. ⁵²

Patients complain of dryness and foreign-body sensation as well as pain and variations in visual acuity due to the resulting irregularity of the corneal surface. Symptoms are often disproportionate to the clinical findings and can be localized to the retrobulbar area; hence they have to be distinguished from pain associated with EO activity. In rare cases, extreme dryness can lead to corneal ulcers and blindness.

Clinical examination shows a diffuse conjunctival injection (to be clinically distinguished from the local injection close to the muscle insertions in active myositis) and conjunctival wrinkling (to be distinguished from chemosis related to inflammation) as well as superficial punctate keratopathy (punctate defects of the corneal epithelium visible with fluorescein stain). Visual acuity can be significantly reduced and simulate a decrease in vision due to optic nerve compression.

Application of artificial tears is the treatment of choice. In severe cases, a temporary closure of the lacrimal drainage system with punctal plugs or a tarsorrhaphy (described below) can be contemplated.

Dry eye can also occur as an initial symptom of EO, so the differential diagnoses should already include EO. ⁵³

7.3.3 Lid Retraction

Upper lid retraction with lateral flare is pathognomonic for EO ( ▶ Fig. 7.6). The resulting staring gaze is described as Kocher’s sign, the visibility of the sclera above the limbus as Dalrymple’s sign.

Lid retraction (enlargement of the palpebral fissure due to retraction of the upper or lower lid margin from the central cornea) in EO is caused by static and dynamic mechanisms. They can affect both the upper and the lower eyelid.

In the course of the disease, the direct involvement of the levator palpebrae superioris muscle leads to fibrosis and static retraction of the upper eyelid. The lower eyelids are accordingly affected on the lower lid retractors (see ▶ Fig. 16.2, ▶ Fig. 16.3).

One of the dynamic mechanisms of a true lid retraction is hyperinnervation of Müller’s muscle in the upper lid (sympathetic part of the capsulopalpebral fascia in the lower lid) due to an increased sympathetic activity in hyperthyroidism.

A true lid retraction is generally visible in primary position, but particularly in downgaze (von Graefe’s sign). This sign can be helpful in distinguishing a pseudo lid retraction.

Infiltration with subsequent fibrosis of the inferior rectus muscle is often part of the muscle involvement in EO. It results in a restrictive vertical strabismus and relative hyperinnervation of the main antagonist, the superior rectus muscle with the co-innervated levator palpebrae superioris muscle (LPS). This leads to an ipsilateral pseudo lid retraction. According to Hering’s law this is followed by hyperinnervation of the contralateral LPS and therefore a contralateral pseudo lid retraction.

Another mechanism causing a pseudo lid retraction is a contralateral ptosis. Here, hyperinnervation of the ipsilateral LPS results in a contralateral upper lid retraction according to Hering’s law. Manual lifting the ptotic eyelid corrects contralateral upper lid retraction. Pseudo lid retraction can also be caused by exophthalmos. Here, the protrusion of the eyeball causes a mechanical enlargement of the palpebral fissure.

For the correction of lid retraction, all these mechanisms have to be considered before lid surgery is planned (Chapter ▶ 7.4.4).

7.3.4 Indicators for Clinical Activity

In the active stage of EO, patients often present with bilateral swelling and redness of the eyelids. Conjunctival injection (hyperemia of the conjunctiva), chemosis (swelling of the conjunctiva), as well as swelling of the caruncle and plica semilunaris often occur in active disease ( ▶ Fig. 7.7). As mentioned before, this has to be distinguished from viral and allergic conjunctivitis as well as from irritation associated with dry eye.

7.3.5 Exophthalmos

The protrusion of the eye from the orbit is defined as exophthalmos (proptosis). EO presents axial proptosis, wherein the globe is displaced anteriorly without any horizontal or vertical displacement. The amount of exophthalmos is usually determined with the Hertel exophthalmometer, in which the position of the corneal apex is measured in relation to the lateral orbital rim in primary gaze (primary position). Hence, absolute values can vary significantly between individuals, depending on facial configuration, and are mainly used for follow-up examination.

A nonaxial protrusion should always raise suspicion regarding the possibility of an extraconal mass in the orbit.

Exophthalmos associated with EO is caused by a proliferation of orbital adipose tissue, swelling of the extraocular muscles, and orbital edema due to increased expression of glycosaminoglycans.

Apart from considerable cosmetic impairment, exophthalmos is the main risk factor for severe exposure keratopathy with corneal ulceration.

7.3.6 Lagophthalmos

Lagophthalmos is mainly caused by lid retraction and proptosis. Incomplete involuntary blinking with complete arbitrary lid closure is described as blink lagophthalmos. The rare blinking, frequently observed in EO, is known as Stellwag’s sign. A history of nocturnal lagophthalmos may be sought from carers and attendants. In assessing lagophthalmos, it is not only its degree that is important but, especially, whether corneal exposure exists. Bell’s phenomenon is an important protective mechanism for the cornea. When closing the lids, the eyeball rotates upward, protecting the cornea under the upper lid. This reflex is suppressed by restriction due to fibrosis of the inferior rectus muscle, as is often the case in EO. In case of corneal exposure, surgical correction of the lagophthalmos is urgently required.

7.3.7 Ptosis

Ptosis can have an aponeurotic cause due to a chronic swelling of the periorbital tissue and stretching of the levator aponeurosis associated with an exophthalmos. However, it can also be a sign of myasthenia gravis that sometimes accompanies EO. According to the literature, 5 to 10% of myasthenia patients present autoimmune thyroiditis, but only 0.2% of patients with autoimmune thyroiditis present myasthenia. ⁵⁴ However, diagnosis is important since the disease can be a vital threat.

Myasthenia should always be suspected in strabismus atypical for EO (exodeviation = outward squinting), and in cases presenting with variability in eyelid position along with strabismus.

7.3.8 Exposure Keratopathy

Exposure keratopathy refers to the severe dryness of the cornea due to incomplete eyelid closure (lagophthalmos). The tear film lubricates the corneal surface and is evenly distributed by blinking. It preserves the optical properties of the cornea, which are the basis for good visual acuity, and protects the integrity of the epithelium against microorganisms. Exposure keratopathy develops when the closure of the eyelid is impaired. In EO it is caused by any combination of lid retraction, proptosis, and reduced Bell’s phenomenon due to restrictive strabismus. Ophthalmic examination includes staining of the cornea with fluorescein sodium. The yellow dye stains exposed basement membrane in case of deepithelialization and is clearly visible in the blue light of a slit lamp. In the early stages of exposure keratopathy, the inferior part of the cornea is often stained in a punctate pattern (superficial punctate keratopathy). Further progression can lead to corneal abrasions with extensive epithelial defects. Infection with bacteria or fungi can lead to corneal ulcers. If stromal melt is severe, an ulcer can lead to a perforation of the cornea with prolapse of intraocular tissue ( ▶ Fig. 7.8). An intraocular extension presents itself as hypopyon and can subsequently result in endophthalmitis (infiltration of the vitreous chamber and possibly the retina), panophthalmitis (inflammation of all ocular structures), and orbital cellulitis.

Exposure keratopathy is thus a serious complication of thyroid ophthalmopathy that necessitates urgent treatment (Chapter ▶ 7.4.4).

7.3.9 Strabismus

Involvement of the extraocular muscles leads to swelling and later fibrosis of affected muscles, with resulting restrictive strabismus. The medial rectus muscle and the inferior rectus muscle are most commonly affected. The restriction becomes most obvious in the opposite direction of gaze, hence in abduction and elevation. Patients initially notice diplopia only in extreme gazes. Later they may present with manifest strabismus and sometimes extreme angle deviation. Other muscles—including the oblique muscles—may also be affected. Cover testing and squint assessment as well as traction testing are performed to diagnose restrictive strabismus. Internal strabismus (esotropia) due to fibrosis of the medial rectus muscle and vertical deviation due to fibrosis of the inferior rectus muscle are most commonly observed ( ▶ Fig. 7.9). Less common is exotropia (diverging strabismus; an exception is myasthenia as shown above). Restrictive eye motility may subsequently lead to an increase in intraocular pressure (IOP) when looking in the opposite direction, which also represents a clinical sign. IOP usually increases in an upward gaze.

Progressive strabismus may be an indicator for disease activity but may also be a sign of an increase in fibrotic remodeling. There are therapeutic approaches to treating involved muscles with botulinum toxin in order to prevent contracture. ⁵⁵ Strabismus surgery is the ultimate corrective treatment choice, but it should only be performed after reaching clinical inactivity, a euthyroid state, and stable squint angles. Since a variation in orbital volume may result in an altered globe position, surgical correction of strabismus in EO should only be carried out after orbital decompression. Strabismus surgery aims at increasing the area of binocular single vision and shifting it into the main field of view (straight and downgaze). Full functionality of the muscle cannot be restored, however.

7.3.10 Compressive Optic Neuropathy

Compressive optic neuropathy is the most serious of all EO complications apart from exposure keratopathy. It occurs only in the active stage of EO and may be an indication for emergency orbital decompression.

Clinical signs are loss of vision, relative afferent pupillary defect (RAPD), visual field loss, and impaired color vision. Funduscopy may show a hyperemic and swollen optic disc, possibly with disc hemorrhages ( ▶ Fig. 7.10). These patients often do not present with pronounced exophthalmos.

7.3.11 Glaucoma

Most studies have not shown increased incidence of glaucoma in patients with thyroid eye disease. However, elevated intraocular pressure is frequently observed and described. The main reason for increased IOP is the elevated venous pressure accompanying EO. The involvement of extraocular muscles and restriction of ocular movement leads to gaze-dependent increase in IOP, which might be overlooked in primary position measurements. ⁵⁶ Regular ophthalmological examination is important to determine the timing for treatment.

Compressive optic atrophy may morphologically resemble glaucomatous optic atrophy.

7.4 Therapy

7.4.1 Immunosuppressive Therapy

George J. Kahaly

Introduction

First to be treated is generally the thyroid dysfunction as this alone often leads to an improvement of the symptoms. ⁵⁷ It should be mentioned at this point that not only does the euthyroidism improve the course of the disease but some thyroid depressants themselves have a positive effect on the immunological reaction of the orbit as well. Methimazole effectively inhibits the formation of free radicals from monocytes. ⁵⁸ Furthermore, a severe EO is often associated not only with thyroid dysfunction but also with the coexistence of a goiter. ⁵⁹ In addition to the drug treatment of the hyperthyroidism, radioactive iodine therapy or a thyroidectomy can be considered. Studies show that radioactive iodine therapy is frequently associated with a deterioration of eye involvement. ^{60,​ 61} Without question, a euthyroid state has to be reached and a hypothyroid metabolic condition must be avoided.

Considering that explanations of the development of the EO are largely based on assumptions, so far no causal therapy regimen is available. Hence, treatment objectives focus on relieving local discomfort, inhibiting autoimmune phenomena within the obit, and preventing possible complications. Local eye conditions, for example, dryness or conjunctivitis, can be treated with ophthalmic solutions or ointment.

Glucocorticoids

It is recommended to use glucocorticoids in the acute phase of the disease. Comparative studies show that 70 to 75% of patients benefit from this kind of treatment. The systemic administration of glucocorticoids can be intravenous or oral, with a significant superiority of the intravenous application regarding the reduction of diplopia and the control of inflammatory processes. The increased effectiveness is accompanied by improved tolerance of treatment. Also, the intravenous bolus treatment involves a considerably lower weight gain and patients perceive the treatment as far less stressful. If the glucocorticoid treatment is continued for more than 3 months, vitamin D replacement therapy (5600 IU weekly) has to be administered. Accompanying bisphosphonate therapy should also be administered in patients who are at risk of osteoporosis.

An active principle of glucocorticoids is the inhibition of the nuclear factor κB (Chapter ▶ 7.1.2), which explains the anti-inflammatory effect of this therapy. ⁶² Randomized studies have shown the superiority of intravenous massive-dose steroid therapy (starting with 0.5 g weekly) for about 12 weeks compared to the oral glucocorticoid therapy (starting with 1 mg/kg bw/day). ⁶³ Injections are superior to oral administration, especially with regard to the treatment of diplopia resulting from motility disorders and the fight against inflammatory processes. The increased effectiveness is accompanied by an improved tolerance of the steroid. This is partly true due to the comparatively rare occurrence of stomach pains and skin problems as well as a significantly lower weight gain during intravenous bolus therapy, which is why patients find the treatment to be far less stressful. In optic nerve involvement with impending visual loss, an initially high-dose intravenous therapy with 500 mg methylprednisolone is recommended for 3 days under close ophthalmic observation. If there is improvement of the symptoms of compression, conservative therapy may follow according to the dosage recommendations given earlier; in the event of another optic neuropathy, surgical intervention is unavoidable.

Retrobulbar steroid injection does not offer any advantages compared to systemic application and rather increases the local complication rate. During intravenous administration it has to be considered that cumulative steroid dosages of >10 g of methylprednisolone are associated with increased liver toxicity: several cases of severe and partly fatal liver failure have been described in this dosage range. A predisposing factor could be preliminary liver damage as part of previous viral hepatitis. ^{64,​ 65,​ 66,​ 67} Also, acute left heart failure has been observed under intravenous steroid therapy in previously clinically unremarkable cardiac patients. ⁶⁸

Nonsteroidal Immunosuppressive Agents

When there is insufficient response to the glucocorticoid medication and/or persistent inflammatory activity, the administration of nonsteroidal immunosuppressive agents is indicated. ⁶⁹ These show successful results particularly regarding the soft tissue involvement; their major disadvantage—apart from the higher cost—is the risk of severe infections, which cannot be excluded. it is true also that such therapy is not yet fully established and requires further clinical trials. The use of these agents is therefore restricted to experienced medical centers.

During the treatment any possible side effects must be thoroughly monitored. Cyclosporine, which is generally used in transplantation medicine, can be successfully administered in cases of severe active EO. Treatment with cyclosporine (3–4 mg/kg bw) in combination with glucocorticoid is successful in serious cases and is superior to glucocorticoid monotherapy with regard to efficacy and relapse prophylaxis. ⁷⁰ Cyclosporine inhibits the transcription of the IL-2 gene and suppresses the TSH receptor antibody production. In the treatment of EO, a low dosage of cyclosporine (3 mg/kg bw) is administered. The aim is to slow down the orbital inflammatory process and to prevent relapses after the glucocorticoid therapy. Liver values, kidney retention parameters, and blood pressure need to be monitored regularly. Patients should avoid alcohol consumption while under therapy.

Treatment with high dosages of immunoglobulin has proven to be effective, but due to the very high treatment costs and the risk of infections it is only rarely used. ⁷¹ Expectations of the success of somatostatin analogues were not realized. ^{72,​ 73,​ 74} As in diagnostics, advantage is taken of the increased expression of somatostatin receptors within the orbit. The response to octreotide therapy can be estimated with reference to previously performed octreotide scintigraphy.

Antioxidants

Free radicals and oxidative processes stimulate the immune process in the thyroid and in the eye sockets and are responsible for a substantial part of the orbital damage. Experiments on cell cultures and in animal models as well as clinical studies have already provided specific indications regarding this concept. The most important antioxidant substances include vitamins (C, E, beta-carotene), omega-3 fatty acids (salmon, fish oils), alpha-lipoic acid, nicotinamide, and selenium in particular. Modulation of the inflammatory activity and the autoaggressive mechanisms by the essential trace element selenium have been observed. A randomized trial has demonstrated the protective effect of selenium regarding the inflammatory changes in autoimmune thyroiditis and thyroid eye disease. ^{75,​ 76} This specific effect of selenium was expected from observations that suggested such immunomodulatory influence. ^{77,​ 78} A significant clinical improvement was also achieved during a double-blind, randomized trial investigating rheumatoid arthritis. ⁷⁹ Nonetheless, reliable proof in the form of controlled clinical studies on the effectiveness of antioxidants is still pending. Given the limited treatment alternatives, the low probability of side effects, and the high tolerance rate, supportive antioxidant therapy is likely to be a useful treatment approach in patients with EO.

Controls and Follow-up

Patients with thyroid eye disease in the active stage should be monitored closely and in interdisciplinary collaboration for early detection of possible deterioration of vision, visual field restriction, or corneal lesions. Using a functional TSH receptor antibody test based on a cell-based bioassay, a deterioration of the EO can be predicted in patients with high levels of simulating TSH receptor antibodies. This information can affect treatment decisions, which should be made only by specialists. The recommended conservative therapy regimen for patients with active EO is shown and explained in ▶ Table 7.7.

7.4.2 Radiotherapy of Endocrine Orbitopathy

H. Christiansen and R. M. Hermann

Its potential for regulating inflammation makes radiation therapy an important component in the treatment of EO. This treatment option is especially interesting as it shows similar effectiveness to the use of glucocorticoids but without their typical side effects.

Nonetheless, radiotherapy can act only in the active stage of the disease (CAS ≥ 3/7). Retrobulbar irradiation has no value in the treatment of an inactive, already fibrotic (“burnt out”) phase of the disease ⁵¹ or in the treatment of a vision-threatening dysthyroid optic neuropathy. ⁴⁰

In assessing available studies, it must be kept in mind that both the inclusion criteria and the end points vary between the individual studies. For some groups, eye motility rates are more important, ⁸⁰ while others focus on determining the exact volumes of intraorbital adipose tissue and eye muscles. ⁸¹

Effectiveness of Radiation

Two prospectively randomized studies demonstrate the significance of radiotherapy ( ▶ Table 7.8). Mourits et al randomized 60 euthyroid patients without diabetes suffering from moderate-to-severe EO (defined as moderate motility disorders and consecutive diplopia or proptosis of ≥23 mm, or moderate to severe eyelid swelling) between 10 × 2 Gy irradiation per working day and 10 × 0 Gy placebo irradiation. ⁸⁰ After 6 months, eye motility improved in 60% of patients in the 20 Gy group compared to 30% in the 0 Gy group (p = 0.04). This was mainly due to a reconstitution of the elevation. In the 20 Gy group the diplopia subsequently significantly improved. Patients also showed an earlier decrease in the clinical activity index of the EO. However, differences in exophthalmos, eyelid swelling, and disease activity were not found upon conclusion of the study.

In a second study, Prummel et al randomized 88 euthyroid patients with mild EO (defined as low motility impairment, low eyelid swelling, proptosis of < 24 mm) also between 20 Gy and 0 Gy placebo irradiation. ⁸² After 6 months, no significant differences between the different treatment measures was found; after 12 months, however, 52% of the 20 Gy group showed significant improvements (particularly regarding motility and diplopia) compared to 27% in the 0 Gy group (p = 0.02). Furthermore, the need for alternative treatments was significantly lower after the 20 Gy therapy (66% vs. 84%, p = 0.049). Yet there were no notable differences between the groups regarding quality of life and prognosis of EO symptomatology in clinical progression (14% vs. 16%).

In a meta-analysis of all available data, a Cochrane review identified an odds ratio of 1.92 (1:27–2.91) regarding the therapy success of orbital radiation compared to placebo irradiation. ⁸³

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