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 Table of Contents  
Year : 2020  |  Volume : 32  |  Issue : 1  |  Page : 10-26

An update on thyroid eye disease: Current knowledge, preferred practice patterns, and future therapies

1 Department of Oculoplasty, Orbit and Ocular Oncology, HORUS Specialty Eye Care, Bengaluru, Karnataka; Department of Oculoplasty, Orbit and Ocular Oncology, Amardeep Eye Care, Kollam, Kerala, India
2 Department of Oculoplasty, Orbit and Ocular Oncology, HORUS Specialty Eye Care, Bengaluru, Karnataka, India

Date of Submission12-Dec-2019
Date of Acceptance13-Dec-2019
Date of Web Publication17-Apr-2020

Correspondence Address:
Fairooz P Manjandavida
Department of Oculoplasty, Orbit and Ocular Oncology, HORUS Specialty Eye Care, Bengaluru - 560 078, Karnataka
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/kjo.kjo_87_19

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Thyroid-associated ophthalmopathy (thyroid eye disease [TED], thyroid-associated orbitopathy, or Graves' orbitopathy) is the most common, yet a complex and poorly understood autoimmune orbital pathology. It occurs in association with systemic dysthyroid states, most commonly presenting with hyperthyroidism, but also occurs in association with hypothyroidism or euthyroidism. Despite the ongoing research, the pathogenesis and effective treatment strategies remain obscure, hence presenting a challenge for the treating ophthalmologist. The ocular presentation can vary from mild disease to severe irreversible sight-threatening complications. Ocular manifestations can follow the thyroid dysfunction, present parallel to it, or seldom precedes it. The ocular disease has its own natural course divided into an active and inactive phase. Scoring individual patients for the severity of disease has been frequently revised. The clinical examination, activity, and severity aid the ophthalmologist to decide the stage of the disease and come up with the treatment strategy for each patient. Management strategies include a multidisciplinary team effort. Recently, we have witnessed a leap to newer targeted biologic therapy that not only improves the course of the disease but also the quality of life of these patients. In this review, we present an update of the current understanding of etiopathogenesis, clinical features, and management options for this common yet challenging orbital inflammatory disease.

Keywords: Autoimmune orbitopathy, Graves' disease, myopathy, orbital decompression, proptosis, thyroid eye disease, thyroid orbitopathy

How to cite this article:
Manjandavida FP, Chahar S. An update on thyroid eye disease: Current knowledge, preferred practice patterns, and future therapies. Kerala J Ophthalmol 2020;32:10-26

How to cite this URL:
Manjandavida FP, Chahar S. An update on thyroid eye disease: Current knowledge, preferred practice patterns, and future therapies. Kerala J Ophthalmol [serial online] 2020 [cited 2023 Feb 6];32:10-26. Available from: http://www.kjophthal.com/text.asp?2020/32/1/10/282663

  Introduction Top

Orbital inflammatory diseases range from a spectrum of specific to nonspecific orbital inflammation. Thyroid eye disease (TED), also known as thyroid ophthalmopathy or thyroid-associated orbitopathy (TAO), is the most common specific orbital inflammatory disorder. It is also the most common cause of bilateral proptosis. TED is a complex autoimmune inflammatory condition believed to be caused by autoantibodies directed against receptors seen on the extraocular muscles (EOMs) and soft tissues of the orbit, leading to changes which can be painful, sight threatening, disfiguring, and debilitating functionally and even psychologically.

Avicenna and Al-Jurjani from Persia first described the association between orbitopathy and goiter in AD 1000 and AD 1110. In 1825, Caleb Parry, an English physician, described a case of a 21-year-old female with nervousness, palpitation, and swelling of thyroid gland.[1] However, the disease was named after Robert James Graves, an Irish physician who published a case of goiter with palpitation and exophthalmos (proptosis) of the eye in a female patient in 1835.[2],[3] Graves' disease thus indicates thyroid orbitopathy with a hyperthyroid state.[2] Not just in hyperthyroid status, TED has been described to be associated with hypothyroid ( first described in 1968 by Wyse et al.) and even euthyroid status.[4] Despite a number of randomized controlled trials and meta-analysis studies, the management of TED remains controversial and no published evidence-based standard protocol exists. The management is largely based on the clinical experience and expertise of the treating specialist.

In this review, we aim to discuss the current knowledge about epidemiology, etiopathogenesis, clinical features, and disease severity scores available that are clinically most useful and analyze the management strategies used by different group of practitioners around the world for this common yet challenging ocular condition.

  Epidemiology and Risk Factors Top

TED is the most common disease affecting the orbit and also the most common cause of bilateral proptosis. Reported incidence of TED is 16/100,000 females and 2.9/100,000 males. The prevalence reported is 0.25% with no ethnic predilection.[5] Higher preponderance in females is related to higher incidence of hyperthyroidism in females. Incidence of TED in pediatric population (<18 years) with Graves' disease is variable and has been reported as 17% by Goldstein et al. and 63% by Chan et al.[6],[7]

Factors influencing the development of TED are:

  1. Dysthyroid state: The majority of patients (80%) who develop TED are hyperthyroid, 10% are hypothyroid, and remaining 5%–10% can even have euthyroid status systemically. Graves' disease is the most common autoimmune disease affecting the thyroid gland, and the most common extrathyroidal site of morbidity is the eye. TED was found to develop in 40% of patient with Graves' disease.[8],[9]
  2. Age and gender: TED is a disease of the young or middle aged but can also affect patients in older age groups. The disease appears 2–6 times more frequently in young women, but severe cases occur more frequently in men more than 50 years. The female predilection for TED is more in mild to moderate disease being 9.3:1 in mild and 3.2:1 in moderate TED. This ratio is reversed at 1:4 in severe TED; older male patients are known to have severe disease course.[10],[11]
  3. Genetic factors: Graves' disease is hereditary, and certain human leukocyte antigens (HLAs) are expressed more in those affected.[12] A study by Akaishi et al. on 81 Brazilian TED patients and 161 normal cohort revealed that patients with major extraocular muscle involvement have a higher frequency of HLA-DRB1*16 allele whereas patients with minor extraocular muscle involvement were found to have a higher frequency of the HLA-DRB1*03 allele.[13] It has been studied that HLA-B8, DR3, and DQA1*0501 haplotypes may increase susceptibility to the disease, and HLA-DRβ1*07 may offer protection.[14]
  4. Environmental factors: Environmental exposure and triggers contribute to the development of TED in 20%–30% cases, smoking being the most important trigger.[15] Smoking is known to increase occurrence of TED by 7–8 times. It is believed that increased production of reactive oxygen species by smoking overwhelms oxidation–reduction, which can stimulate orbital fibroblast proliferation in a dose-dependent manner. Cawood et al. proved that orbital fibroblasts when exposed to cigarette extract have a dose dependent statistically significant increase in glycosaminoglycan (GAG) production and adipogenesis.[16],[17] Cessation of smoking can reverse the risk and also leads to better response to treatment.[18]
  5. Treatment for hyperthyroidism: Specific treatment available for treating thyroid dysfunction, namely oral medication, radioactive iodine (RAI) treatment, or surgical thyroidectomy, may impact the course of thyroid-associated ophthalmopathy. Radioactive iodine treatment involves administration of an iodine molecule that gets absorbed by any cell that imports iodine internally including cells in the thyroid gland and the orbit. This results in a powerful inflammatory response that can both worsen existing TED by 15%–39% over antithyroid medication or thyroidectomy, increases the risk of dysthyroid optic neuropathy (DON), or even increase the probability of development of TED in patients who do not have ocular manifestation.[19],[20]
  6. Autoimmunity: There can be an increased prevalence and a relative risk of coexisting autoimmune disorders, for example, rheumatoid arthritis, pernicious anemia, systemic lupus erythematosus, Addison's disease, coeliac disease, and vitiligo.

  Pathogenesis Top

Pathological changes in thyroid eye disease

Pathological changes in TED involves extraocular muscles and the orbital fat.[21] These changes occur due to deposition of GAG, predominantly hyaluronan (HA) within the muscles.[22] The increase in orbital pressure leads to venous outflow congestion and chronic periorbital edema. Histological examination of extraocular muscles shows diffuse and focal lymphocytic infiltrates and fibrosis. Orbital fat and connective tissues also contain infiltrating cells but fewer than those seen in the muscles.[23],[24]

Effector cells in thyroid eye disease

The key effector cells are orbital fibroblasts.[25] In TED patients, a heterogeneous population of orbital fibroblasts exists that can differentiate into mature adipocytes or myofibroblasts.[8],[26] These cells are responsible for producing extracellular matrix and HA and also for interaction with mononuclear cells leading to production of chemoattractants and cytokines that cause orbital inflammation, fibrosis, and tissue remodelling. This manifests into adipogenesis, HA synthesis, interstitial edema, and enlargement of extraocular muscles-key changes that lead to clinical manifestations of TED. It is believed that the heterogeneous presentations of thyroid orbitopathy could be due to cellular divergence of these fibroblasts within the orbit.[27]

Molecular mechanism underlying thyroid eye disease

The association of hyperthyroidism and eye changes led to the hypothesis of thyroid and orbital tissue sharing a common antigen. Exact antigens are still not known but proposed antigens are thyroglobulin, thyroid-stimulating hormone receptor (TSH-R), and insulin-like growth factor receptor (IGF-1R). Study of TED in hypothyroid states and euthyroid states has brought forward the role of extraocular muscle antigen calsequestrin and orbital connective tissue antigen collagen XIII in the pathogenesis.[12],[28],[29] IGF-1R and TSH-R form a physically and functionally interactive complex within orbital fibroblasts. IGF-1R overexpression appears central to disease pathogenesis.[30]

The pathway for fibroblast activation was summarized by Lehman et al.[31] The cross-reactivity against antigens underlies the autoimmune ophthalmic response. Activated fibroblasts release chemokines which recruit T-lymphocytes into the orbit, leading to a cascade of inflammatory response. The resulting cytokine production and secretion of T-cell activating factors leads to extracellular matrix deposition, fibroblasts proliferation, and adipogenesis.

  Course of the Disease: Rundle's Curves Top

Sustained activity in an autoimmune disease requires lymphoid neogenesis. The orbit lacks lymphoid tissue, and hence, TED is typically self-limiting in nature. The disease has an inflammatory, active phase that can have rapidly worsening symptoms and signs, usually subsiding over one to 2 years (range 6 months to 5 years) which gives way to a static plateau phase which is the fibrotic, inactive phase. In this phase, gradual improvement of inflammatory signs can be seen; but, it is important to note that disease does not return to the baseline, rather permanent fibrotic changes occur. These permanent structural changes in the eye might require treatment. These phases can be plotted graphically for each patient describing the natural history of the disease and is called Rundle's curve[32] [Figure 1]. Since its first description in 1957, although theoretical, this curve has been useful in providing context to judge therapeutic interventions and a chronology to counsel TED patients. “Active” disease implies the presence of acute inflammatory features, relates to the early phases in Rundle's curve, and the potential for response to medical treatments. “Inactive” defines the phase when only surgical treatment can alter outcome.
Figure 1: Rundle's curve depicting the natural course of thyroid eye disease. The dynamic phase corresponds to the active, inflammatory state and, static phase corresponds to the inactive, fibrotic state

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  Clinical Features Top


Most patients, who are young or middle aged females, present with concurrent thyrotoxicosis. About 10%–20% develop ocular problems in months before becoming thyrotoxic and about 10%–15% present with the current or previous hypothyroidism.


Common early symptoms include altered periocular appearance, grittiness, photophobia, excessive lacrimation due to dry eyes, and retrobulbar dull aching pain. Visual disturbances include double vision or blurred vision.


Ophthalmic findings are generally bilateral and mostly asymmetrical. More than 90% of patients with TED have ocular surface abnormalities and eyelid changes. In a cohort of 120 TED patients, clinical features described were eyelid retraction – 91%, exophthalmos – 62%, extraocular muscle dysfunction – 43%, ocular pain – 30%, lacrimation – 23%, and optic nerve disease – 6%.[33]


Eyelid retraction affecting 90%–98% of patients is the most characteristic finding. Contour of the retracted upper eyelid shows “lateral flare” which is almost pathognomonic of TED.[34],[35] Increased sympathetic stimulation of Muller's muscle, contraction of levator muscle, and scarring between the lacrimal gland fascia and levator are proposed mechanisms for these lid changes. The excursion of upper eyelid lagging behind eyeball movement on vertical downward pursuit (lid lag) and incomplete eyelid closure (lagophthalmos) are important signs to note[36],[37] [Figure 2]. In a study by Lim et al. in Southeast Asian population, lower eyelid retraction was found to be more common (44.3%) than upper eyelid retraction (40.8%) which was similar to findings of Lim et al. in Malaysian population.[38],[39]
Figure 2: (a) Unilateral proptosis of right eye in a 32-year-old lady showing eyelid retraction, lateral flare and, superior and inferior scleral show. (b) Downgaze lid lag is characteristic of thyroid eye disease along with other features

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Some eponyms associated with Graves' disease are described in [Table 1].
Table 1: List of eponyms associated with ocular changes seen in Grave's disease

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Ocular surface disease

The poor function of the eyelid–tear–cornea interface causes ocular surface manifestations in 45%–85% of patients of TED.[40] In the early-active phase, inflammatory molecules attack mucous-producing cells, tear gland, and corneal surface, causing breakdown of tear film manifesting as soft tissue inflammation presenting as dilated conjunctival vessels, superior limbic keratitis, keratoconjunctivitis, and corneal changes. In the stable phase, chronic exposure due to inability to close the eye completely leads to dryness.

Extraocular muscles

Deposition of GAG causes enlargement of the EOMs. The inflammation and scarring cause strabismus and limited motility manifesting as pulling sensation in the eyes in mild cases; but, in advanced stage, it results in horizontal, vertical, and torsional strabismus. The double vision that ensues can be the most debilitating consequence, especially if present in downgaze and primary gaze. Inferior rectus involvement can also lead to a poor Bell's phenomenon, which can increase the risk of corneal exposure.


Increased volume of orbital soft tissue due to changes in the orbital fat, muscle, and fibrous tissue in the setting of unyielding bony confines of the orbit can cause protrusion of the eyeball, which is called proptosis. Poor venous drainage due to this congestion behind the globe can lead to redness and swelling of the eyelids, chemosis, and caruncular congestion. In advanced cases, this increased pressure can result in increased intraocular pressure causing glaucoma. Occasionally, brow fat swelling and cheek swelling is noted which has been described as thyroid-associated periorbitopathy (TAP).[41],[42]

Ocular emergencies in thyroid eye disease

Ocular emergencies encountered are optic neuropathy, corneal ulceration and perforation, subluxation of the globe, and severe periorbital edema and chemosis.

In severe inflammatory states, the expanded soft tissue of the orbit and the muscle enlargement at the apex of the orbit may lead to compression of the optic nerve causing vision-threatening complication – DON[43] [Figure 3].
Figure 3: (a) A 68-year-old male who is a chronic smoker with bilateral active severe thyroid eye disease, presenting with afferent pupillary defect in both eyes. (b and c) Computed tomography scan depicts enlarged extraocular muscles with crowding at the apex in axial and coronal view

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About 60% of TED patients will have mild discomfort related to eyelid retraction, 35% suffer from diplopia or disfiguring proptosis, and about 3%–7% develop the vision threatening complication such as DON.[43] The degree of proptosis does not correlate with DON, as it is the enlarged EOM, which expands to compress the optic nerve rather than producing exophthalmos.[44] Optic neuropathy signs include decrease in visual acuity, visual field, color vision, and afferent pupillary defect, which might be absent if the condition is bilateral. Fundus examination can reveal optic disc edema. If not treated, it can result in optic atrophy and permanent visual loss. Since patients can develop DON after their clinical evaluation or may have equivocal diagnosis of DON on presentation, efforts have been made to develop list of findings to identify “at risk” patients which includes significantly reduced extraocular motility, ptosis, significant effacement of perineural fat, and more recently described the medial rectus volume and higher inflammation score in vision, inflammation, strabismus, and appearance (VISA).[45],[46] Some authors have demonstrated enlargement of superior ophthalmic vein as predictor for concomitant optic neuropathy.[47]

Exposure keratopathy can occur due to lid retraction, lagophthalmos, and proptosis. This coupled with tear film abnormalities can cause keratitis. Severe cases can develop corneal ulceration, perforation, and secondary endophthalmitis. If urgent actions are not taken, catastrophic loss of vision can occur.

A study by Chng et al. emphasizes that clinical presentation differs between ethnic groups and TED is less common and less severe in Asians but is associated with higher risks of corneal complications and DON.[48] A study of TED in Southeast Asian patients by Lim et al. cited that the most common presentation was eyelid retraction (62.1%), followed by proptosis (61.0%) and only 4.6% developed optic neuropathy. Corneal erosion secondary to acquired epiblepharon was a common sign in Asian patients.[38]

  Disease Activity and Severity Top

Disease activity refers to active inflammation where gradual progressive worsening of symptoms and signs can be seen. Disease severity describes the functional or cosmetic deficit at any stage. Determining the phase of TED helps in formulating an appropriate management plan. Medical management is effective only in active inflammatory phase. In the inactive phase, no inflammation is present, but residual fibrosis persists, and if required, only surgical treatment can alter outcome.

Assessment of thyroid eye disease

Several classification systems have been proposed to assess the clinical manifestations of TED [Table 2]. Werner in 1969 devised a mnemonic NO SPECS to document disease severity.[49] Modified NO SPECS was published by Werner in 1977 and is broadly used since then[50] [Table 3]. This classification, however, grades clinical severity but does not distinguish active inflammatory phase from inactive phase, and indication for treatment was decided only according to the severity of the disease.
Table 2: Disease activity and severity grading systems: The evolution

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Table 3: Modified NO SPECS classification

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In 1989, Mourits et al. described the Clinical Activity Score (CAS).[51] This score discriminates between the active and quiescent stage of the disease as it is based on the classical signs of inflammation (pain, redness, swelling, and impaired function). This was further modified in 1997[52] [Table 4]. Modified CAS is used to evaluate disease activity, and score out of 10 is given. A score of 3 or less is considered as inactive and 4 or more is considered as active eye disease at first examination. A score of 4 or more on follow-up examination indicates active disease. This scoring criterion has the disadvantage of being subjective in nature with a large interobserver variation. The advantage lies in its easy applicability in everyday clinical practice.
Table 4: Clinical Activity Score amended by European group on Graves' Orbitopathy

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The other grading systems used are VISA classification and the European group on Graves' Orbitopathy (EUGOGO) classification.[53],[54],[55],[56] These systems use specific indicators to assess signs of activity and degree of severity and hence act as a guide for the treatment protocol for a specific patient.

The VISA system was developed by Dolman and Rootman in 2006 and was adopted with modifications by the International TED Society (ITEDS) [Table 5]. The current version that can be used for office is available for download from ITEDS website (http://www.thyroideyedisease.org/). Each section records subjective inputs and measurable objective inputs. This helps direct appropriate management for patients with TED in a logical sequence depending on aspect of the disease affecting them.[53],[54] The EUGOGO was established in 1999. This is widely used in Europe and is based on activity and severity parameters [Table 6]. An image  Atlas More Details developed by the group aids in evaluating severity parameters. New patient and follow-up forms, together with the color atlas, are available for download from the EUGOGO website (http://www.eugogo.eu/).[55],[56]
Table 5: Vision, Inflammation, Strabismus, and Appearance classification with recommended clinical evaluation for thyroid eye Disease

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Table 6: The European Group on Graves' Orbitopathy severity assessment

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Both VISA and EUGOGO systems are assessment with practical implications for guiding management of patients, which was missing in earlier classifications by Werner. These two classification systems are not interchangeable. VISA is widely used in United States and Canada and EUGOGO in Europe.

  Clinical Investigation Top

Detailed clinical history and thorough clinical examination are the first steps in evaluation of a patient on presentation and cannot be substituted. Clinical investigations aid in diagnosis and monitoring treatment of TED.

  1. Photographic documentation: Comparison of old and most recent pictures helps identify approximate onset of eye disease. This documentation can also help in comparison and improvement after treatment is started
  2. Biochemical investigations: Orbital signs may precede thyroid dysfunction, hence thyroid hormone levels must be evaluated in every case to ensure euthyroid status. Endocrine evaluation includes free triiodothyronine (T3), free thyroxine (T4), serum TSH, thyroid-stimulating immunoglobulin, thyroid peroxidase antibody, and TSH receptor antibody. Assessment of TSH is single most useful test in majority of patients to determine hyper/hypothyroidism. Measurement of serum free T3 levels and free T4 levels can determine the degree of hyperthyroidism when serum TSH levels are suppressed.
  3. Orbital imaging: Orbital imaging can be performed using a computed tomography (CT) scan or a magnetic resonance imaging (MRI) scan. CT is more sensitive than MRI in identifying enlarged extraocular muscles (85.4% for CT vs. 61.2% for MRI as described in a study by Polito and Leccisotti).[57]

Axial and coronal slices with 2 mm cuts should be requested as a standard. Typical radiological features seen in TED on CT are muscle belly enlargement, classically described as “tendon sparing” (Coca-Cola bottle sign), an increase in orbital fat volume, and crowding of the optic nerve at the orbital apex in severe cases [Figure 4]. Stretch neuropathy characterized by a “taut” nerve can be identified in severe cases. Enlarged and anteriorly displaced lacrimal glands suggesting vascular engorgement and inflammation can also be noted. The differences in orbital tissue densities allow for high-resolution imaging even without intravenous (IV) contrast administration. Contrast when used can better delineate optic nerve pathology.[58] However, CT remains a relatively inexpensive (compared to MRI), fast, and highly reproducible imaging modality in TED. Although MRI is more specific for optic nerve imaging, CT scan can also be used to diagnose optic neuropathy. CT provides a better imaging of bony anatomy of the orbit which is invaluable in preoperative setting while preparing for orbital decompression.[58],[59]
Figure 4: Computed tomography imaging in thyroid eye disease. (a) Axial view on computed tomography scan showing enlarged medial rectus typically sparing the tendons “coca-cola bottle” sign. (b) Medial rectus enlargement increases the risk of optic nerve compression, as seen in the figure in the right eye. (c and d) Coronal view on computed tomography scan depicting enlargement of extraocular muscles suggesting thyroid myopathy

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CT scans can help evaluate the type of orbitopathy. CT scan-based classification includes type 1 orbitopathy (lipogenic variant): involvement of only adipose tissue, type 2 orbitopathy (myogenic variant): involvement of extraocular muscle, and type 3 orbitopathy (mixed): wherein enlargement of both orbital fat compartment and extraocular muscle is seen.[60]

MRI scan provides a high-quality anatomical detail of the orbit. In the active phase, EOM appear isointense in T1-weighted images and hyperintense in T2 weighted images whereas in chronic phase they appear hypointense in T2-weighted images.[58] The longer T2 relaxation time on MRI is a senstive marker for demonstarting edema within the recti and orbital fat.[61]

  Management Strategies Top

The management plan for each patient is individually designed as it precisely depends on the stage of the disease and the severity of the disease. Patients should be managed by a coordinated team of oculoplastic/orbit surgeon, strabismologist, neuro-ophthalmologist, endocrinologist, and radiologist. Most important step is to identify patients likely to have serious complications as vision-threatening optic neuropathy or severe corneal exposure keratopathy. The current regimens for treatment of TED show wide regional variations, and there are still no set protocol for the choice and timing of the modalities.

General measure for all patients

  1. Restore euthyroid status: Euthyroidism should be restored as early as possible. The modality of treatment might include antithyroid drugs, radioiodine, or thyroidectomy. More than the modality of choice, the final goal of euthyroid status is of prime importance. However, use of RAI can worsen the course of active disease, and hence, it is important that the treating ophthalmologist works in collaboration with endocrinologist[62]
  2. Cessation of smoking
  3. General symptomatic conservative measures: This includes head elevation in sleep to reduce periorbital edema, use of sunglasses to avoid photophobia, and use of artificial tear drops to keep ocular surface moist.

Measures for patients with mild thyroid eye disease

Local measures are the mainstay therapy for mild TED. Studies have proven that in untreated mild TED, orbitopathy improved in 50%, remained stable in 35%, and worsened in approximately 5%.[63]

Oral selenium administration (dose of 100 μg of sodium selenite twice daily taken for 6-months) has been analyzed in a study and seen to improve quality of life, reduce ocular involvement, and slow down the progression of disease with mild TAO.[64] However, the study did not measure baseline selenium levels in the study population and changes in the levels after administration. Diabetes is also a known risk factor in patients treated with selenium supplementation. Hence, in routine practice, specialists seldom use oral selenium for mild TED. Use of oral corticosteroids is usually not recommended in mild TAO, and oral nonsteroidal anti-inflammatory drugs can be used to reduce inflammation present. Definitive surgery for lid retraction in mild TAO during active phase is contraindicated. Rehabilitative surgery if required in case of lid retraction should be considered when TAO becomes stable and inactive.[65],[66]

Measures for patients with moderate to severe thyroid-associated orbitopathy

Moderate to severe disease has sufficient impact on daily life to warrant treatment, which includes immunosuppression in active phase and surgical intervention in inactive stage.

In active disease, immunosuppression is the mainstay of treatment. This includes corticosteroids, steroid-sparing immunosuppressive therapy, or orbital radiation. It is important to note that immunosuppression can act only in the active phase of the disease and has no benefit for quiescent phase wherein fibrotic changes have set in the orbital tissue.[66]

Immunosuppression with steroids

Steroid therapy has been used in TED through oral, local, or IV routes. Oral therapy requires higher doses with prolonged period of treatment and is associated with frequent flare-up of disease on tapering. Starting dose 80–100 mg prednisolone (or 1 mg/Kg body weight) followed by weekly taper (10 mg/week) has been seen to be beneficial. No randomized placebo-controlled studies have been performed, but open trials or randomized studies comparing oral steroids with other treatment show a favorable response in 33%–63% patients particularly for soft tissue changes, recent onset eye muscle involvement, and compressive optic neuropathy.[53],[67],[68],[69] Side effects are frequent, and long-term use is associated with a risk of osteoporosis. Oral corticosteroids can be used if IV infusion is not logistically possible, in case the patient prefers the oral route or in situ ations when the determination of activity is uncertain.[70] Local steroids (retrobulbar or subconjunctival) is less effective than oral therapy.[70],[71] However, studies evaluating peribulbar triamcinolone injections have shown favorable results.

A comparative study of IV corticosteroids versus oral glucocorticoids by Zang et al. has shown favorable results for IV corticosteroids, the overall response rate being 82% for IV steroids as compared to 53.4% for oral steroids. The pulses of IV steroids were seen to be associated with fewer side effects, shorter treatment course, and lower relapse risk compared with oral steroids. It was also seen that the use of oral steroids between IV pulses and its use after did not increase the response rate.[72] IV-pulsed methylprednisolone was the preferred therapeutic approach for active moderate to severe TED as seen in a survey conducted by Sundar et al. in Asia-pacific region and according to the consensus statement by EUGOGO.[55],[73],[74] A survey among members of American Society of Ophthalmic Plastic and Reconstructive surgery (ASOPRS) revealed that IV steroids was used as a second-line treatment by most specialist (74.2%).[75]

IV steroid regimen preferences vary according to the clinical experience of the treating specialist. No randomized control trials exist for optimum treatment protocol. IV methylprednisolone (IVMP) is the preferred choice [Figure 5]. The commonly used protocol in our clinical practice is 6 pulses of high-dose IVMP (500 mg/day for 3 days, followed by 500 mg single dose 2 weekly for a total of 6 pulses). EUGOGO protocol (500 mg weekly for 6 weeks followed by 250 mg weekly for another 6 weeks, for a cumulative dose of 4.5 g) is also popular among practitioners.[76]
Figure 5: (a) Bilateral moderate thyroid eye disease in a 38-year-old female at presentation. (b) Shows complete resolution of symptoms and signs after intravenous methylprednisolone pulse therapy

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The dosage preferred by oculofacial surgeons in South-East Asia was 1 g/day for 3 days, for 1–4 cycles.[73] A majority of members of ASOPRS preferred weekly dosing (61%), over daily dosing (28%) whereas 11% also chose the option of “every other day” dosing.[75] Consensus statement from EUGOGO also states that IV steroids have a higher response rate than oral steroids (80% vs. 50%), but the evidence for superiority of any schedule of IVMP is lacking. The statement also emphasizes that treatment should be undertaken in centers with appropriate expertise.[55],[74] A prospective randomized trial by Zhu et al. also proved that weekly protocol of IVMP is more efficient and safer than daily protocol.[77]

The cumulative dose of IV methylprednisolone that is safe is 8 g, and higher doses can result in significant morbidity and can prove to be fatal. Liver toxicity with IVMP can be fatal side effect. Essential investigations before IV steroids administration are blood sugar workup, baseline blood pressure, liver function tests including hepatitis viral markers, and autoantibodies with or without sonography for liver morphology. Patients with recent hepatitis, liver dysfunction, severe cardiovascular morbidity, or severe hypertension must be excluded.

Steroid-sparing immunosuppressive therapy

Many steroid-sparing immunosuppressive drugs have been attempted given the autoimmune nature of TED. Role of cyclosporine has been well evaluated. Cyclosporine has been shown to work synergistically when used with glucocorticoids (Cyclosporine A 5 mg/kg/day in 2 doses plus oral glucocorticoids). Regular monitoring of side effects is required, the most common and concerning side effect being sterility.[78] Methotrexate given in a dose of 5–25 mg once per week can be beneficial, although no randomized clinical trials exist.[79],[80]

Rituximab, a monoclonal antibody-targeting CD 20+ B cells and a subset of T cells of the immune system, has been tried as an alternative treatment for refractory TED. The early clinical results based on the studies show encouraging results of rituximab to reduce inflammatory activity and disease severity. Available dosing regimens for rituximab include four consecutive weekly IV infusions of 375 mg/m2 of body surface area (typically used for hematologic disorders) or two IV infusions of 1000 mg given 2 weeks apart (typically used in autoimmune disease).[81],[82]

Rituximab has been generally well tolerated. Most common side effects seen are related to infusion, including hypotension. Arthralgia has been reported. However, limited evidence suggests that rituximab may cause or aggravate inflammatory bowel disease such as ulcerative colitis.[83],[84] Long-term follow-up in studies revealed no relapse of inflammatory orbital disease in rituximab group probably due to persistent blood B-cell depletion.

Other biological immunosuppressive agents shown to be effective in TED are etanercept, adalimumab, and tocilizumab. Infliximab might be useful in severe TED with optic nerve compression resistant to steroid and decompression.[85]

Teprotumumab has emerged as a novel therapy after completion of multicenter phase 2 and phase 3 clinical trials, which specifically targets the molecular causes of TED. It inhibits IGF-1R and blocks signaling from TSH-R/IGF-1R signaling complex, thus reducing the orbital fibroblast HA production and cytokine stimulation.[32],[86]

Orbital radiotherapy

Orbital radiotherapy has a nonspecific anti-inflammatory effect. The lymphocytes infiltrating the orbit are seen to be highly radiosensitive, and it reduces the secretion of pro-inflammatory cytokines from activated lymphocytes. The secretion of GAG is suppressed by the effect of radiations on the downstream chain of fibroblast activation by inducing terminal differentiation in progenitor fibroblasts.[87] The reported response rate of orbital radiotherapy in open trials is 60%. Recommended dosage is 10–20 Gy in 10 sessions, over 2 weeks. Radiotherapy side effects for this dose are known to be mild. Visually most devastating consequence, although uncommon, is radiation optic neuropathy. It is reported with total radiation dose >50 Gy and/or a daily radiation fraction size >2 Gy. The efficacy of orbital radiotherapy in combination with glucocorticoids has been proven to be better than orbital radiotherapy alone and has an acceptable safety profile.[88] When used in combination, steroids act immediately to suppress the acute inflammation that may not be taken care by orbital radiotherapy as it takes several weeks to start its action. This is particularly effective in ocular motility involvement and in some cases, in DON. Survey by Sundar et al. revealed that 12.8% of respondents in South east Asia preferred orbital radiotherapy in their practice as compared to 1.7% of respondents from ASOPRS using it as a first-line treatment therapy.[73]

Measures for severe sight-threatening thyroid eye disease

Impending compressive optic neuropathy or severe disc edema mandates immediate attention. Severe proptosis leading to stretch neuropathy also requires medical or surgical intervention to avoid visual compromise. Optimum treatment of optic neuropathy is high-dose IVMP (1 gm/day for 3 days, followed by 500 mg single-dose 2 weekly for a total of 6 pulses or titrated accordingly) without exceeding the cumulative dosage. Prompt surgical decompression should be considered when response to medical treatment is inadequate. The main objective is to relieve the hydrostatic pressure at the orbital apex and hence reducing orbital congestion and improve vascular perfusion and axonal flow within the optic nerve and improve its function. Surgically, this is achieved by decompression of the posteromedial orbit. The surgical approach can be endonasal or transconjunctival retrocaruncular.

Exposure keratopathy is another potential sight-threatening condition, which requires immediate attention. It can lead to corneal ulceration, perforation, and secondary endophthalmitis causing catastrophic loss of vision. Surgical options depend on degree of proptosis and control of thyroid activity. In case of active TED, intensive topical lubricants should be started for corneal protection. Urgent lid lowering by levator complex recession can be considered keeping in mind the unpredictable nature of surgery in acute phase and need for a correction of height and contour in future if required. Temporary suture tarsorrhaphy can be considered. Injection botulinum toxin to levator palpebrae superioris can induce temporary blepharoptosis and corneal protection. In the quiescent phase, orbital decompression can be considered with lid lowering by levator complex recession.

Surgical intervention

If there is evidence that the disease has been quiescent for 6 months, rehabilitative surgery for moderate to severe TED may be used. Four components that require attention are proptosis, restrictive strabismus, eyelid abnormality (retraction), and cosmetic concerns. The four stages of surgical rehabilitation in the order performed are: (1) orbital decompression, (2) extraocular muscle surgery, (3) eyelid repositioning, and (4) cosmetic soft tissue redraping.[89]

First stage: Orbital decompression

The principle is to expand the orbital space by removing the excessive orbital fat and/or widening the bony orbit, thus relieving the venous congestion and mechanical pressure on optic nerve and reducing proptosis. The aim is to increase the orbital volume for the increased orbital content, which can thus expand into the newly created space leading to globe retraction and reduction in proptosis.

Typically, the first approach is to remove orbital fat known as fat removal orbital decompression (FROD) and if required proceed to bony wall, known as bone removal orbital decompression (BROD). Advances in surgical techniques allow the oculoplastic/orbital surgeon to have a minimally invasive approach to these locations while maximizing cosmesis.[90],[91],[92] FROD is effective for mild (2–3 mm) proptosis, and it can be the primary procedure or combined with BROD [Figure 6]. In BROD, the thumb rule followed is that each orbital wall provides 2 mm reduction in proptosis. Hemostasis is the most important point to remember as fat in TED is very vascular wherein after excision, the bleeders might retract and bleed in the orbit.[92]
Figure 6: (a) A 21-year-old male with right eye inactive thyroid eye disease at presentation. (b) There is improved cosmesis after fat removal orbital decompression, lower lid retractor release, and mullerotomy with levator recession

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Anatomically, four walls are available, but orbital roof decompression, although performed by Nafzigger, is best avoided given the serious complications involved. Lateral wall decompression has been considered as primary approach for moderate proptosis. An eyelid crease incision or swinging eyelid incision gives a good approach for accessing the deep lateral wall (sphenoid bone).[93] Goldberg et al. have described the three areas of deep bone in the lateral orbital conceptually designating them as lacrimal key hole, the sphenoid door jamb, and the basin of the inferior orbital fissure. In their experience, every 1 cm3 of bone removed results in 0.8 mm of proptosis reduction. This technique causes less postoperative strabismus and eliminates risk of sinusitis.[93],[94]

Medial wall decompression can be approached through transcaruncular, skin (Lynch), or endonasal approach.[95],[96] Orbital floor decompression is accessed through transconjunctival incision, or a subciliary skin incision or transantral (Caldwell-Luc) approach. Risk of infraorbital nerve damage causing anesthesia and hypoglobus needs to be kept in mind.[97],[98]

For moderate to severe proptosis, balanced decompression including medial and lateral wall gives better outcome as compared with unbalanced decompression of medial wall and floor. A balanced decompression is thought to prevent inferomedial displacement of the globe and produce an equal prolapse of the medial and lateral rectus muscles into the surrounding space. However, preservation of the inferomedial orbital strut can prevent most of the complications associated with an unbalanced orbital decompression, whether performed transconjunctivaly or endonasally.[98],[99],[100] However, a retrospective review by Goldberg etal. comparing 25 balanced decompression with 38 lateral wall decompression suggested that preoperative strabismus resolved spontaneously in 25% of balanced decompression group, compared to 60% in lateral wall decompression group. In addition, persistent new-onset postoperative strabismus occurred in 33% of balanced group and only 7% of lateral group[93],[94] [Figure 7].
Figure 7: (a and b) A 60-year-old male with unilateral severe sight-threatening active thyroid eye disease of the left eye. Severe proptosis, chemosis, and corneal exposure are evident clinically. (c-e) Left eye shows significant reduction in proptosis and orbital congestion after surgical management by balanced bone reduction orbital decompression

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In the presence of severe proptosis where 6-8 mm reduction is required, 3-wall decompression is adviced. This includes deep lateral wall followed by medial wall and orbital floor. The potential complications include infraorbital anesthesia due to nerve injury, new-onset strabismus, optic nerve injury, and sometimes cerebrospinal fluid leak. Equipment such as the piezoelectric technology that emulsifies bone without harming the soft tissue is of great help in preventing inadvertent soft tissue trauma.[101]

The individual outcomes of exophthalmos reduction are unpredictable influenced by: (a) peribulbar fat tissue “stiffness” and hence the readiness for herniation into new space, (b) the ratio of muscle to fat hypertrophy, and (c) individual orbital morphology and size.[102],[103]

Second stage: Strabismus surgery to relieve diplopia

This usually follows orbital decompression, unless only mild proptosis is present wherein decompression can be avoided. Most commonly, recession of tight muscles is carried out using adjustable sutures. Patient needs to be counseled well for realistic results and achievement of binocular single vision. Important to note is the lower eyelid retraction, which results due to recession of the inferior rectus muscle.[104]

Third stage: Eyelid abnormality

Lid surgery might be required to tackle corneal exposure or to improve cosmesis.

Lid retraction (upper or lower lid) is the most common feature in TED. Nonsurgical management options include botulinum toxin injection, a neurotoxin to weaken the Muller's muscle function, the effect being short lived. Mancini et al. used injection of hyaluronic acid gel fillers to induce a relative mechanical ptosis for minor asymmetries.[105] Surgery is indicated if retraction >1 mm, there is asymmetry of palpebral apertures, or lateral (temporal) flare. Surgery includes recession of Muller's muscle or levator aponeurosis.[106],[107],[108] Hintschich et al. reported that 95% of operated lids achieved a perfect or acceptable result following full-thickness blepharotomy.[109] Important point to keep in mind while addressing retraction is the lateral flare.[110],[111] A careful preoperative contour evaluation is essential to achieve the correct lid height and a normal, smooth contour. Lower eyelid retraction, which has been described to be more common in Asian patients with TED, can be corrected with recession or actual extirpation of inferior retractors. The use of spacer grafts to lengthen lower eyelid height is also well reported. Kikkawa et al. reported an overall positive effect of graded orbital decompression on eyelid position postoperatively, with 1.3 mm and 1.6 mm decrease in upper and lower eyelid retraction following orbital decompression that achieved an average of 5.7 mm of proptosis reduction.[112] Recent emerging reports suggest combining various stages of surgeries to minimize the number of rehabilitative procedures required. A review by Norris et al. suggested that combining decompression with inferior retractor recession is safe and improves lower lid height post operatively.[113]

Other esthetic concerns for periocular manifestation of TED like deep glabellar folds can be treated with botulinum toxin injection into the concerned muscles (corrugator supercilii).

Management of pediatric thyroid eye disease

It is known to have milder clinical manifestations and lesser frequency of sight threatening complications that seldom requires treatment, stabilizes, and eventually resolves without intervention [Table 7].[114]
Table 7: Thyroid eye disease in pediatric population

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Overall, a number of tools exist in the armamentarium of the treating specialist for TED. According to a recent network meta-analysis, IV steroids and teprotumumab were considered as best strategy for proptosis reduction.[115] In 2016, EUGOGO consensus statement suggested that high-dose IV steroids should be considered as a first-line treatment for moderate to severe and active TED.[55],[73] Orbital injection ranked behind IV steroids. Orbital radiotherapy, though known to have a good response, is not used routinely by many specialists. Survey of ASOPRS showed that while 70% of specialist used orbital radiation, only 2% used it as first line, 20% as second line, and 33% as third line treatment.[75] Somatostatin analogs have shown good result in trials and Rituximab has been recognised as a promising biological agent. Management strategies may differ according to the clinical experience of the treating specialist, patient population, and access to resources [Table 8] and [Table 9].[73],[74],[75]
Table 8: Comparison of survey of preferred practice patterns among oculofacial surgeons in Asia - Pacific region and registered members of American Society of Ophthalmic Plastic and Reconstructive Surgery

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Table 9: Summary of consensus statement by European Group on Graves' Orbitopathy on management of Grave's orbitopathy

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Brief summary of practice pattern followed by the authors is elicited in [Figure 8].
Figure 8: The overview of treatment preferred by the authors for thyroid eye disease

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  Conclusion Top

TED is the most common cause of proptosis in adults. It is a complex, self-limiting autoimmune inflammatory disease of the orbit with a heterogeneous presentation and variable systemic dysthyroid states. Meticulous clinical examination, grading the activity, and severity of the disease help in deciding a tailored management strategy for each patient. Multidisciplinary team efforts provide the best possible care for the patients. Most important step is to identify potential sight-threatening disease stage to offer prompt treatment. Inspite of the ongoing research and evolving novel therapeutic target therapies, this entity remains challenging for the treating physician.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8]

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9]

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