Thyroid eye disease: a review

Transcription

1 CLINICAL AND EXPERIMENTAL REVIEW Thyroid eye disease: a review Clin Exp Optom 2017; 100: Danielle L Weiler* OD FAAO *Optometry Section, Southern Arizona Veterans Affairs Health Care System, Tucson, Arizona, USA Southern California College of Optometry, Fullerton, California, USA Danielle.Weiler@va.gov Submitted: 4 May 2016 Revised: 27 June 2016 Accepted for publication: 16 July 2016 DOI: /cxo Thyroid eye disease is a multifactorial autoimmune disease with a spectrum of signs and symptoms. Oftentimes, the diagnosis of thyroid eye disease is straightforward, based upon history and physical examination. The purpose of this review is to assist the eye-care practitioner in staging the severity of thyroid eye disease (mild, moderate-to-severe and sightthreatening) and correlating available treatment modalities. Eye-care practitioners play an important role in the multidisciplinary team by assessing functional vision while also managing ocular health. Key words: Graves ophthalmopathy, Graves orbitopathy, thyroid eye disease Thyroid eye disease, also called Graves ophthalmopathy or Graves orbitopathy, is an autoimmune disorder of the retrobulbar tissue most commonly associated with Graves hyperthyroidism (Graves disease); however, patients may be hypothyroid or euthyroid. Thyroid eye disease may precede or follow endocrine manifestations but they tend to present within 18 months of each other in 80 per cent of patients. 1,2 Thyroid eye disease and Graves hyperthyroidism can occur at any age but women in their third to fifth decade of life are more commonly affected. 1,3 Despite this, the severity of thyroid eye disease tends to be worse in men and in patients who are first diagnosed when they are over 50 years old. 4,5 The estimated incidence of thyroid eye disease is 16 women and three men per 100,000 population per year. 4,6 Several risk factors have been identified, including cigarette smoking, 7 10 older age at diagnosis of Graves hyperthyroidism, 4,8 longer duration of Graves hyperthyroidism, 8 uncontrolled thyroid dysfunction 11 and prior radioactive iodine treatment. 8,12 Oftentimes, the diagnosis of thyroid eye disease is straightforward based upon history and physical examination. Ophthalmic manifestations are present in up to 50 per cent of Graves hyperthyroidism patients. 1,13 Thyroid eye disease follows a biphasic course: a progressive or active phase lasting up to three years followed by a stable or inactive phase. 14,15 Ophthalmic manifestations can vary from mild (for example, dry eye) to sightthreatening (for example, corneal ulceration and compressive optic neuropathy) with management varying from supportive (for example, ocular surface lubrication) to surgical (for example, orbital decompression). Due to the varying clinical presentations, there is a wide range of diseases in the differential diagnosis, including allergic conjunctivitis and orbital tumours. This review will assist the eye-care practitioner in staging the severity of thyroid eye disease (mild, moderateto-severe and sight-threatening) and correlating available treatment modalities. Additionally, it is important that eye-care providers do not overlook the functional or visual complaints of patients with thyroid eye disease, and therefore, the treatment of these complaints will also be discussed. PATHOPHYSIOLOGY Thyroid eye disease is a complex autoimmune disease with the pathogenesis becoming more clearly understood; however, it is not completely comprehended. While the underlying molecular mechanism of thyroid eye disease is multifaceted, the activation of autoantibodies to thyroid stimulating hormone (TSH, thyrotropin) receptors (TSHR) seems to be the inciting event. 1,2 In patients with Graves hyperthyroidism, there is an over-expression of TSHR in the retrobulbar tissue compared to controls, particularly in orbital fibroblasts, 16 which are integral in the pathogenesis of thyroid eye disease. 1,16 18 Upon activation, orbital fibroblasts proliferate and secrete pro-inflammatory cytokines and hydrophilic hyaluronan into the interstitial space. 1,16,17 These processes result in a large osmotic pressure gradient in the orbit, leading to increased fluid accumulation between the muscle fibres. Additionally, some orbital fibroblasts differentiate into mature adipocytes causing expansion of the orbital adipose tissue. 2,16,18 This cycle perpetuates and orbital congestion can ensue. 16,17 Long-lasting oedema leads to atrophy, fibrosis and sclerosis of the extraocular muscles subsequently causing restrictive strabismus. 15 CLASSIFICATION Because thyroid eye disease manifests as a spectrum of symptoms and signs, no single test can be used to assess disease severity. 19 Werner s NO SPECS mnemonic (Table 1) has been used broadly to classify thyroid eye disease since its inception in 1969 and modification in ,21 While the mnemonic is helpful in outlining the clinical signs of thyroid eye disease, it is a poor indicator for severity and progression of thyroid eye disease. 20,21 Mouritis and colleagues 22 proposed the Clinical Activity Score (CAS) in 1989 to distinguish between the active and inactive stages (Table 2). In 2006, Dolman and Rootman 23 and later Dolman 14 introduced the Clinical and Experimental Optometry January Optometry Australia

2 Class Signs Category Symptoms Recommended clinical evaluation 0 No symptoms or signs 1 Only signs, no symptoms (lid retraction and stare) 2 Soft tissue involvement (conjunctival and caruncle injection and chemosis; eyelid erythema, oedema and fullness) 3 Proptosis 4 Extraocular muscle involvement 5 Corneal involvement 6 Sight loss (optic nerve involvement) Table 1. Werner s NO SPECS classification 20,21 Item Parameters assessed 1 Spontaneous retrobulbar pain 2 Pain on attempted upward or downward gaze 3 Eyelid erythema 4 Eyelid oedema 5 Conjunctival hyperaemia 6 Conjunctival chemosis 7 Inflammation of caruncle or plica Table 2. Clinical Activity Score (CAS). One point given for each parameter present. Classified as inactive if CAS is less than three and active if CAS is three or more. 22 VISA classification to determine clinical activity based upon descending order of importance: vision, inflammation, strabismus and appearance (Table 3). 14,23 The European Group on Graves Orbitopathy (EUGOGO) first published a consensus statement in ,25 and recently updated their management guidelines in light of emerging clinical trials. 26 The EUGOGO stages are outlined in Table 4. While both VISA and EUGOGO are grounded in NO SPECS and CAS, they are not interchangeable, with VISA more commonly used in North America and EUGOGO in Europe. 15 Regardless of the system used to stage thyroid eye disease, both VISA and EUGOGO classifications have practical implications for management. Vision Visual blurring Visual acuity with manifest refraction Colour desaturation Colour vision Pupil responses Optic nerve evaluation Standardised perimetry Neuroimaging Possible visual evoked potential Inflammation Orbital aching at rest or with movement External and slit-lamp evaluation to score: Eyelid or conjunctival swelling Orbital pain Eyelid or conjunctival redness Chemosis Eyelid oedema Conjunctival injection Eyelid injection Strabismus Diplopia Extraocular movements Appearance No diplopia CLINICAL ASSESSMENT With horizontal or vertical gaze Intermittent in primary gaze Constant in primary gaze Distress about bulging eyes, eyelid retraction and/or fat pockets Dry eye symptoms There is no single clinical finding or laboratory test that is diagnostic of thyroid eye disease. Frequently, the presenting symptoms are non-specific dry eye complaints, such as foreign body sensation, redness, blurring of vision, photophobia, glare or excessive tearing; 6,17,23,27 however, there are many additional symptoms, including concern about cosmesis, retrobulbar discomfort, swelling of the eyelids worse in the morning, diplopia and uncommonly loss of vision. 14,23 Common clinical signs are upper eyelid retraction, conjunctival and caruncle Versions, ductions and forced ductions Head posture Cover testing in diagnostic action fields Field of binocular single vision External eyelid evaluation Eyelid retraction Lid lag and von Graefe s sign testing Lagophthalmos Scleral show Presence of redundant skin and fat prolapse Exophthalmometry Slit-lamp examination Table 3. VISA classification 23 with adapted recommended clinical evaluation for thyroid eye disease injection and/or oedema, eyelid oedema and/or erythema with diurnal variation, ocular motility disruption or strabismus and proptosis. 13,14,17 Paradoxically, upper eyelid ptosis can also be a presenting sign of thyroid eye disease. 28 The clinical evaluation for thyroid eye disease focuses upon determining clinical activity and severity by assessing visual acuity, pupils, colour vision, extraocular movements, visual field, exophthalmometry, external eyelid evaluation, slit-lamp examination and dilated fundus examination. The correlating clinical sign for each of these examination components is outlined in Table Optometry Australia Clinical and Experimental Optometry January

3 Stage Mild thyroid eye disease Moderate-to-severe thyroid eye disease Sight-threatening thyroid eye disease Features Minor impact on activities of daily living Insufficient justification for immunosuppression or surgical treatment One or more of the following: Minor lid retraction (less than 2 mm) Mild soft tissue involvement Proptosis less than 3 mm above normal for race and gender No or transient diplopia Corneal exposure responsive to lubricants Impact on activities of daily living Justification for immunosuppression and/or surgical treatment Two or more of the following: Lid retraction 2 mm or more Moderate or severe soft tissue involvement Proptosis 3 mm above normal for race and gender Diplopia (inconstant or constant) Compressive optic neuropathy Corneal ulceration Table 4. The European Group on Graves Orbitopathy severity assessment and magnetic resonance imaging (MRI) can confirm the diagnosis of thyroid eye disease while excluding other diagnoses such as orbital tumour and idiopathic orbital inflammation (previously known as orbital pseudotumour). Computerised tomography without contrast remains the standard radiographic technique because of its ability to display the bony anatomy of the orbit and its low cost relative to MRI. 19 As iodinated contrast dye can induce or exacerbate thyrotoxicosis, its use is contraindicated in patients with thyroid eye disease. 32 With imaging studies, the extraocular muscle bellies are enlarged with relative sparing of the tendons, whereas in orbital myositis the tendons are also enlarged. Typically, there is asymmetric bilateral involvement of extraocular muscles affected in the following pattern: inferior recti, medial recti, superior recti, lateral recti and the obliques (Figure 1). When compressive optic neuropathy from orbital apex crowding is suspected, MRI is the imaging study of choice. 6 MANAGEMENT When compared to controls, patients with Graves hyperthyroidism have a significantly higher frequency (p < 0.01) of eyelid retraction (38 per cent), von Graefe s sign (36 per cent) and lagophthalmos (16 per cent) but not true lid lag (eight per cent, p = 0.67). 29 Thus, detecting incomplete lid closure (that is, lagophthalmos) in addition to observing the position of the upper eyelid in relation to the superior limbus in primary gaze (that is, lid retraction), in downgaze (that is, lid lag) and with dynamic downward movement (that is, von Graefe s sign) is crucial when evaluating these patients. Normal exophthalmometric values vary depending upon race; the upper normal limit for globe protrusion is 18.6 mm for Asian males, 21.7 mm for White males and 24.7 mm for Black males. 30,31 In general, adult females across all races have lower exophthalmometry values compared to their male counterparts. 6 A difference greater than 2.0 mm between the two eyes of any given patient is considered abnormal. 6 Forced duction testing is indicated when the extraocular movement is restricted. Unlike in cranial nerve paresis, restriction from thyroid eye disease would not result in improved movement with forced duction testing. Additional clinical testing that could assist in differentiating other causes of binocular diplopia are the cover test and/or Maddox rod testing in the nine diagnostic action fields and Park s three-step for vertical diplopia. ADDITIONAL DIAGNOSTIC TESTING Laboratory testing is indicated to screen for thyroid dysfunction; however, some patients who present with thyroid eye disease may not have abnormalities in thyroid screening tests. 6 The recommended initial screening for suspected hyperthyroidism is concomitant serum free T4, free or total T3 and TSH. 3 When considered in conjunction with thyroid eye disease, simultaneously elevated free T4 and decreased TSH levels are usually sufficient to confirm the diagnosis of hyperthyroidism. 3 In patients with suspected thyroid eye disease and normal thyroid screening tests, additional laboratory studies may uncover euthyroid thyroid eye disease: TSH-receptor antibodies (TRAb), thyroid-binding inhibitory immunoglobulins (TBII), thyroid-stimulating immunoglobulins (TSI) and antimicrosomal antibody (also known as thyroid peroxidase antibody, TPO). 6 Imaging studies of the orbit such as ultrasonography, computed tomography (CT) Thyroid dysfunction Optimal management of thyroid eye disease requires a multidisciplinary approach between eye-care providers and primary care, internal medicine or endocrinology. 26,33 The primary treatment should restore and sustain a euthyroid state. 3,34 There are three main treatment options: anti-thyroid drugs, thyroidectomy and radioactive iodine. 13 In the United States, the therapy of choice to restore normal thyroid function has been radioiodine therapy; 35 however, reports have linked radioiodine therapy to causing or exacerbating thyroid eye disease in about 15 to 20 per cent of patients, the majority of whom are smokers. 3 The use of prophylactic oral corticosteroids following radioiodine therapy may reduce the risk of development or progression of thyroid eye disease. 33,36 While reducing thyroid hormone secretion does not improve the underlying pathology of thyroid eye disease, eyelid retraction may improve. 37 Cessation of smoking The association between smoking and thyroid eye disease is well established Smoking cessation is the most important modifiable Clinical and Experimental Optometry January Optometry Australia

4 without side effects. As knowledge of the immunopathogenesis of thyroid eye disease grows, steroid-sparing biologic agents, like rituximab, have shown promise in treatment of thyroid eye disease. 41,44 Despite this, two small-scale randomised trials of rituximab in moderate-to-severe thyroid eye disease report conflicting results. 45,46 Currently, there are no pure target agents available and large-scale randomised clinical trials are lacking. 44 Figure 1. Magnetic resonance imaging (T1-weighted coronal image) showing bilateral asymmetric non-uniform enlargement of inferior and medial recti risk factor in the prevention and progression of thyroid eye disease. 38 Smokers have 2.47 greater odds of thyroid eye disease than nonsmokers. 8 Furthermore, current smokers are at increased odds compared to former smokers 8 with increased thyroid eye disease severity dependent upon the number of cigarettes per day in current smokers. 7,9 EUGOGO recommends smoking cessation counselling for all thyroid eye disease patients regardless of severity Conservative treatment Local supportive measures such as use of preservative-free ocular lubricants, moisture chambers and taping eyelids should be prescribed for all patients with dry eye symptoms. 2,34 Approximately two-thirds of patients with mild disease spontaneously improve within six months, so no treatment beyond supportive therapy is necessary. 2 Sunglasses can improve photosensitivity and glare. Fresnel prism or monocular occlusion can resolve diplopia in the active phase. If diplopia is mild in the inactive phase, prism correction can be incorporated into the patient s glasses. The treatment goal of diplopia is primary gaze single vision. Finally, botulinum toxin injection to the levator palpebrae superioris and Müller muscle complex may be considered to mitigate upper eyelid retraction. 39 Medical treatment In a randomised, placebo-controlled trial of patients with mild thyroid eye disease, selenium supplementation was shown to improve quality of life, reduce severity and slow the progression in patients with mild thyroid eye disease; 40 however, criticisms of this study have been that serum selenium levels were not measured during the study and it is unknown whether the study population had a baseline selenium deficiency compared to other populations. 33,40,41 A subsequent casecontrolled study found serum selenium levels are lower in patients with thyroid eye disease compared to patients with Graves hyperthyroidism without thyroid eye disease. 42 Additional studies are needed to fully understand the role of selenium in the pathogenesis of thyroid eye disease. Oral and intravenous corticosteroids have been the mainstay of treatment for patients with moderate-to-severe active thyroid eye disease for their anti-inflammatory properties. 39,41 High-dose intravenous corticosteroids are effective in nearly 80 per cent of patients. 43 While highly effective and safer than oral corticosteroids, their use is not Orbital radiation Orbital radiation has been used in the treatment of thyroid eye disease for nearly a century; however, its role remains controversial. 47 Orbital radiotherapy is generally well tolerated and safe 48 but is relatively contraindicated in patients under 35 years or with systemic vascular disease. 39,49 Orbital fibroblasts are sensitive to ionising radiation, reducing the proliferation of effector cells. 41,48 Several reports have shown orbital radiotherapy can enhance the effects of corticosteroids and allow for a shorter duration of corticosteroid use while improving ocular signs Thus, orbital radiotherapy should be considered a second-line treatment when corticosteroids have only produced a partial response and the disease is still active. 15,26 Therapy for sight-threatening thyroid eye disease Patients with compressive optic neuropathy and/or severe corneal exposure have sightthreatening thyroid eye disease. Recognition of these patients is paramount for timely management. 26,39 Unexplained deterioration of vision, altered colour vision in one or both eyes, globe subluxation, corneal opacification, recent development of choroidal folds and optic disc oedema suggest sightthreatening thyroid eye disease. 26,39 The EUGOGO recommendation for patients with compressive optic neuropathy includes high-dose intravenous corticosteroids with urgent orbital decompression if there is little or no response to corticosteroids. 26 In severe cases of corneal exposure, frequent topical lubricants may not be sufficient to prevent ulceration, thinning and perforation. 39 In these cases, moisture chambers, 26,39 topical cyclosporine, 52 topical or subconjunctival corticosteroids, 53 bandage soft contact lenses, therapeutic scleral contact lenses, amniotic membranes or tarsorrhaphy 26,39 may be used to promote corneal healing. Orbital decompression is 2016 Optometry Australia Clinical and Experimental Optometry January

5 indicated if these measures fail to protect the cornea. 26,39 Surgical rehabilitation Surgical rehabilitation is indicated for patients with moderate-to-severe inactive thyroid eye disease when there is a significant impact on visual function or quality of life. 26,41 The general surgical sequence employed in inactive thyroid eye disease is orbital decompression, followed by extraocular muscle surgery, with eyelid procedures performed last. 2 Several approaches of orbital bone decompression have been studied along with the number of orbital walls removed. Thus far, the superiority of one method over the others has not been established. 2 In a series of 78 patients who had transantral or endonasal bone decompression, proptosis was reduced by 4.4 to 4.7 mm, visual acuity improved in 44 to 55 per cent of subjects and diplopia persisted in 50 per cent of subjects but was improved in 54 per cent of those subjects. 54 In a different series, 28 per cent of patients experienced resolution of diplopia following orbital bone decompression. 55 Orbital fat decompression can be combined with bone decompression or performed alone for reduction of proptosis and improvement in diplopia. 56,57 Exposure keratopathy can be treated with temporary tarsorrhaphy while awaiting orbital decompression. 34 Extraocular muscle surgery (strabismus surgery) is considered in cases where diplopia persists or worsens following orbital decompression. 2 Eyelid surgery is performed last for symptomatic eyelid retraction or asymmetric lid position with the goal of maintaining adequate corneal coverage. 2 Quality of life Quality of life questionnaires, both general health-related and disease-specific, have been studied in thyroid eye disease patients. Both indicate markedly impaired quality of life in patients with thyroid eye disease. 58 It has been argued that quality of life should be considered the most important indicator of treatment success, when the primary goal of treatment is to improve daily function rather than to prolong life. 58 Moreover, it is important to remember that the same degree of thyroid eye disease can have different impacts on the well-being of different patients. 58 In a cross-sectional study, successful treatment of diplopia with prism in adults with strabismus improved quality of life. 59 ACKNOWLEDGEMENTS The author thanks Amy Grimes OD and Tina Porzukowiak OD for their thoughts and assistance with editing this manuscript. REFERENCES 1. Douglas RS, Gupta S. The pathophysiology of thyroid eye disease: implications for immunotherapy. Curr Opin Ophthalmol 2011; 22: Stan MN, Garrity JA, Bahn RS. The evaluation and treatment of graves ophthalmopathy. Med Clin North Am 2012; 96: Bartalena L. 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