|Year : 2020 | Volume
| Issue : 1 | Page : 10-26
An update on thyroid eye disease: Current knowledge, preferred practice patterns, and future therapies
Fairooz P Manjandavida1, Shaifali Chahar2
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 Submission||12-Dec-2019|
|Date of Acceptance||13-Dec-2019|
|Date of Web Publication||17-Apr-2020|
Fairooz P Manjandavida
Department of Oculoplasty, Orbit and Ocular Oncology, HORUS Specialty Eye Care, Bengaluru - 560 078, Karnataka
Source of Support: None, Conflict of Interest: None
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 2022 Jan 21];32:10-26. Available from: http://www.kjophthal.com/text.asp?2020/32/1/10/282663
| Introduction|| |
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. 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., Graves' disease thus indicates thyroid orbitopathy with a hyperthyroid state. 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. 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|| |
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. 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.,
Factors influencing the development of TED are:
- 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.,
- 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.,
- Genetic factors: Graves' disease is hereditary, and certain human leukocyte antigens (HLAs) are expressed more in those affected. 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. 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.
- Environmental factors: Environmental exposure and triggers contribute to the development of TED in 20%–30% cases, smoking being the most important trigger. 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., Cessation of smoking can reverse the risk and also leads to better response to treatment.
- 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.,
- 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|| |
Pathological changes in thyroid eye disease
Pathological changes in TED involves extraocular muscles and the orbital fat. These changes occur due to deposition of GAG, predominantly hyaluronan (HA) within the muscles. 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.,
Effector cells in thyroid eye disease
The key effector cells are orbital fibroblasts. In TED patients, a heterogeneous population of orbital fibroblasts exists that can differentiate into mature adipocytes or myofibroblasts., 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.
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.,, IGF-1R and TSH-R form a physically and functionally interactive complex within orbital fibroblasts. IGF-1R overexpression appears central to disease pathogenesis.
The pathway for fibroblast activation was summarized by Lehman et al. 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|| |
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 [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|
Click here to view
| Clinical Features|| |
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%.
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., 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, [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.,
|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|
Click here to view
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|
Click here to view
Ocular surface disease
The poor function of the eyelid–tear–cornea interface causes ocular surface manifestations in 45%–85% of patients of TED. 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.
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).,
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 [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|
Click here to view
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. 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. 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)., Some authors have demonstrated enlargement of superior ophthalmic vein as predictor for concomitant optic neuropathy.
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. 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.
| Disease Activity and Severity|| |
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. Modified NO SPECS was published by Werner in 1977 and is broadly used since then [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.
In 1989, Mourits et al. described the Clinical Activity Score (CAS). 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 [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|
Click here to view
The other grading systems used are VISA classification and the European group on Graves' Orbitopathy (EUGOGO) classification.,,, 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., 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/).,
|Table 5: Vision, Inflammation, Strabismus, and Appearance classification with recommended clinical evaluation for thyroid eye Disease|
Click here to view
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|| |
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.
- 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
- 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.
- 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).
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. 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.,
|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|
Click here to view
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.
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. The longer T2 relaxation time on MRI is a senstive marker for demonstarting edema within the recti and orbital fat.
| Management Strategies|| |
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
- 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
- Cessation of smoking
- 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%.
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. 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.,
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.
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.,,, 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. Local steroids (retrobulbar or subconjunctival) is less effective than oral therapy., 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. 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.,, 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%).
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.
|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|
Click here to view
The dosage preferred by oculofacial surgeons in South-East Asia was 1 g/day for 3 days, for 1–4 cycles. 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. 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., A prospective randomized trial by Zhu et al. also proved that weekly protocol of IVMP is more efficient and safer than daily protocol.
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. Methotrexate given in a dose of 5–25 mg once per week can be beneficial, although no randomized clinical trials exist.,
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).,
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., 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.
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.,
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. 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. 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.
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.
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.
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.,, 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.
|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|
Click here to view
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). 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.,
Medial wall decompression can be approached through transcaruncular, skin (Lynch), or endonasal approach., 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.,
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.,, 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, [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|
Click here to view
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.
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.,
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.
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. 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.,, Hintschich et al. reported that 95% of operated lids achieved a perfect or acceptable result following full-thickness blepharotomy. Important point to keep in mind while addressing retraction is the lateral flare., 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. 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.
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].
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. 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., 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. 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].,,
|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|
Click here to view
|Table 9: Summary of consensus statement by European Group on Graves' Orbitopathy on management of Grave's orbitopathy|
Click here to view
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|
Click here to view
| Conclusion|| |
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.
| References|| |
Parry CH. In: Collected works, vol 1. Ed Underwood, London 1825. pp 478-80.
Bahn RS. Graves' ophthalmopathy. N
Engl J Med 2010;362:726-38.
Marketos SG, Eftychiadis A, Koutras DA. The first recognition of the association between goiter and exophthalmos. J Endocrinol Invest 1983;6:401-3.
Wyse EP, McConahey WM, Woolner LB, Scholz DA, Kearns TP. Ophthalmopathy without hyperthyroidism in patients with histologic Hashimoto's thyroiditis. J Clin Endocrinol Metab 1968;28:1623-9.
Lazarus JH. Epidemiology of Graves' orbitopathy (GO) and relationship with thyroid disease. Best Pract Res Clin Endocrinol Metab 2012;26:273-9.
Goldstein SM, Katowitz WR, Moshang T, Katowitz JA. Pediatric thyroid-associated orbitopathy: The children's hospital of Philadelphia experience and literature review. Thyroid 2008;18:997-9.
Chan W, Wong GW, Fan DS, Cheng AC, Lam DS, Ng JS. Ophthalmopathy in childhood Graves' disease. Br J Ophthalmol 2002;86:740-2.
Prabhakar BS, Bahn RS, Smith TJ. Current perspective on the pathogenesis of Graves' disease and ophthalmopathy. Endocr Rev 2003;24:802-35.
Burch HB, Wartofsky L. Graves' ophthalmopathy: Current concepts regarding pathogenesis and management. Endocr Rev 1993;14:747-93.
Bartley GB. The epidemiologic characteristics and clinical course of ophthalmopathy associated with autoimmune thyroid disease in Olmsted county, Minnesota. Trans Am Ophthalmol Soc 1994;92:477-588.
Bartley GB, Fatourechi V, Kadrmas EF, Jacobsen SJ, Ilstrup DM, Garrity JA, et al
. The incidence of Graves' ophthalmopathy in Olmsted County, Minnesota. Am J Ophthalmol 1995;120:511-7.
Ardley M, McCorquodale T, Lahooti H, Champion B, Wall JR. Eye findings and immunological markers in probands and their euthyroid relatives from a single family with multiple cases of thyroid autoimmunity. Thyroid Res 2012;5:4.
Akaishi PM, Cruz AA, Silva FL, Rodrigues Mde L, Maciel LM, Donadi EA. The role of major histocompatibility complex alleles in the susceptibility of Brazilian patients to develop the myogenic type of Graves' orbitopathy. Thyroid 2008;18:443-7.
Lee HB, Rodgers IR, Woog JJ. Evaluation and management of Graves' orbitopathy. Otolaryngol Clin North Am 2006;39:923-42, vi.
Hansen PS, Brix TH, Iachine I, Kyvik KO, Hegedüs L. The relative importance of genetic and environmental effects for the early stages of thyroid autoimmunity: A study of healthy Danish twins. Eur J Endocrinol 2006;154:29-38.
Pryor WA, Stone K. Oxidants in cigarette smoke. Radicals, hydrogen peroxide, peroxynitrate, and peroxynitrite. Ann N
Y Acad Sci 1993;686:12-27.
Cawood TJ, Moriarty P, O'Farrelly C, O'Shea D. Smoking and thyroid-associated ophthalmopathy: A novel explanation of the biological link. J Clin Endocrinol Metab 2007;92:59-64.
Krassas GE, Wiersinga W. Smoking and autoimmune thyroid disease: The plot thickens. Eur J Endocrinol 2006;154:777-80.
Stan MN, Bahn RS. Risk factors for development or deterioration of Graves' ophthalmopathy. Thyroid 2010;20:777-83.
Bartalena L, Marcocci C, Bogazzi F, Manetti L, Tanda ML, Dell'Unto E, et al
. Relation between therapy for hyperthyroidism and the course of Graves' ophthalmopathy. N
Engl J Med 1998;338:73-8.
Garrity JA, Bahn RS. Pathogenesis of Graves ophthalmopathy: Implications for prediction, prevention, and treatment. Am J Ophthalmol 2006;142:147-53.
Pappa A, Jackson P, Stone J, Munro P, Fells P, Pennock C, et al
. An ultrastructural and systemic analysis of glycosaminoglycans in thyroid-associated ophthalmopathy. Eye (Lond) 1998;12 (Pt 2):237-44.
Kroll AJ, Kuwabara T. Dysthyroid ocular myopathy. Anatomy, histology, and electron microscopy. Arch Ophthalmol 1966;76:244-7.
Weetman AP, Cohen S, Gatter KC, Fells P, Shine B. Immunohistochemical analysis of the retrobulbar tissues in Graves' ophthalmopathy. Clin Exp Immunol 1989;75:222-7.
Wang Y, Smith TJ. Current concepts in the molecular pathogenesis of thyroid-associated ophthalmopathy. Invest Ophthalmol Vis Sci 2014;55:1735-48.
Smith TJ, Koumas L, Gagnon A, Bell A, Sempowski GD, Phipps RP, et al
. Orbital fibroblast heterogeneity may determine the clinical presentation of thyroid-associated ophthalmopathy. J Clin Endocrinol Metab 2002;87:385-92.
Kuriyan AE, Woeller CF, O'Loughlin CW, Phipps RP, Feldon SE. Orbital fibroblasts from thyroid eye disease patients differ in proliferative and adipogenic responses depending on disease subtype. Invest Ophthalmol Vis Sci 2013;54:7370-7.
Lahooti H, Parmar KR, Wall JR. Pathogenesis of thyroid-associated ophthalmopathy: Does autoimmunity against calsequestrin and collagen XIII play a role? Clin Ophthalmol 2010;4:417-25.
McCorquodale T, Lahooti H, Gopinath B, Wall JR. Long-term follow-up of seven patients with ophthalmopathy not associated with thyroid autoimmunity: Heterogeneity of autoimmune ophthalmopathy. Clin Ophthalmol 2012;6:1063-71.
Chen H, Mester T, Raychaudhuri N, Kauh CY, Gupta S, Smith TJ, et al
. Teprotumumab, an IGF-1R blocking monoclonal antibody inhibits TSH and IGF-1 action in fibrocytes. J Clin Endocrinol Metab 2014;99:E1635-40.
Lehmann GM, Garcia-Bates TM, Smith TJ, Feldon SE, Phipps RP. Regulation of Lymphocyte Function by PPARgamma: Relevance to Thyroid Eye Disease-Related Inflammation. PPAR Res. 2008;2008:895901.
Rundle FF. Management of exophthalmos and related ocular changes in Graves' disease. Metabolism 1957;6:36-48.
Bartley GB, Fatourechi V, Kadrmas EF, Jacobsen SJ, Ilstrup DM, Garrity JA, et al
. Clinical features of Graves' ophthalmopathy in an incidence cohort. Am J Ophthalmol 1996;121:284-90.
Lebensohn JE. The eye signs of Graves' disease. Am J Ophthalmol 1964;57:680-1.
Waller RR. Eyelid malpositions in Graves' ophthalmopathy. Trans Am Ophthalmol Soc 1982;80:855-930.
Frueh BR, Musch DC, Garber FW. Lid retraction and levator aponeurosis defects in Graves' eye disease. Ophthalmic Surg 1986;17:216-20.
Werner SC. Classification of the eye changes of Graves' disease. Am J Ophthalmol 1969;68:646-8.
Lim NC, Sundar G, Amrith S, Lee KO. Thyroid eye disease: A Southeast Asian experience. Br J Ophthalmol 2015;99:512-8.
Lim SL, Lim AK, Mumtaz M, Hussein E, Wan Bebakar WM, Khir AS. Prevalence, risk factors, and clinical features of thyroid-associated ophthalmopathy in multiethnic Malaysian patients with Graves' disease. Thyroid 2008;18:1297-301.
Nowak M, Marek B, Kos-Kudła B, Kajdaniuk D, Siemińska L. Tear film profile in patients with active thyroid orbithopathy. Klin Oczna 2005;107:479-82.
Goldberger S, Sarraf D, Bernstein JM, Hurwitz JJ. Involvement of the eyebrow fat pad in Graves' orbitopathy. Ophthalmic Plast Reconstr Surg 1994;10:80-6.
Kim BJ, Kazim M. Prominent premalar and cheek swelling: A sign of thyroid-associated orbitopathy. Ophthalmic Plast Reconstr Surg 2006;22:457-60.
Neigel JM, Rootman J, Belkin RI, Nugent RA, Drance SM, Beattie CW, et al
. Dysthyroid optic neuropathy. The crowded orbital apex syndrome. Ophthalmology 1988;95:1515-21.
McKeag D, Lane C, Lazarus JH, Baldeschi L, Boboridis K, Dickinson AJ, et al
. Clinical features of dysthyroid optic neuropathy: A European Group on Graves' Orbitopathy (EUGOGO) survey. Br J Ophthalmol 2007;91:455-8.
Weis E, Heran MK, Jhamb A, Chan AK, Chiu JP, Hurley MC, et al
. Clinical and soft-tissue computed tomographic predictors of dysthyroid optic neuropathy: Refinement of the constellation of findings at presentation. Arch Ophthalmol 2011;129:1332-6.
Weis E, Heran MK, Jhamb A, Chan AK, Chiu JP, Hurley MC, et al
. Quantitative computed tomographic predictors of compressive optic neuropathy in patients with thyroid orbitopathy: A volumetric analysis. Ophthalmology 2012;119:2174-8.
Lima Bda R, Perry JD. Superior ophthalmic vein enlargement and increased muscle index in dysthyroid optic neuropathy. Ophthalmic Plast Reconstr Surg 2013;29:147-9.
Chng CL, Seah LL, Khoo DH. Ethnic differences in the clinical presentation of Graves' ophthalmopathy. Best Pract Res Clin Endocrinol Metab 2012;26:249-58.
Werner SC. The eye changes of Graves' disease: Overview. Mayo Clin Proc 1972;47:969-74.
Werner SC. Modification of the classification of the eye changes of Graves' disease. Am J Ophthalmol 1977;83:725-7.
Mourits MP, Koornneef L, Wiersinga WM, Prummel MF, Berghout A, van der Gaag R. Clinical criteria for the assessment of disease activity in Graves' ophthalmopathy: A novel approach. Br J Ophthalmol 1989;73:639-44.
Mourits MP, Prummel MF, Wiersinga WM, Koornneef L. Clinical activity score as a guide in the management of patients with Graves' ophthalmopathy. Clin Endocrinol (Oxf) 1997;47:9-14.
Dolman PJ. Evaluating Graves' orbitopathy. Best Pract Res Clin Endocrinol Metab 2012;26:229-48.
Dolman PJ, Rootman J. VISA classification for Graves orbitopathy. Ophthalmic Plast Reconstr Surg 2006;22:319-24.
Bartalena L, Baldeschi L, Dickinson A, Eckstein A, Kendall-Taylor P, Marcocci C, et al
. Consensus statement of the European Group on Graves' orbitopathy (EUGOGO) on management of GO. Eur J Endocrinol 2008;158:273-85.
Polito E, Leccisotti A. MRI in Graves orbitopathy: Recognition of enlarged muscles and prediction of steroid response. Ophthalmologica 1995;209:182-6.
Kahaly GJ. Imaging in thyroid-associated orbitopathy. Eur J Endocrinol 2001;145:107-18.
Kirsch E, Hammer B, von Arx G. Graves' orbitopathy: Current imaging procedures. Swiss Med Wkly 2009;139:618-23.
Regensburg NI, Kok PH, Zonneveld FW, Baldeschi L, Saeed P, Wiersinga WM, et al
. A new and validated CT-based method for the calculation of orbital soft tissue volumes. Invest Ophthalmol Vis Sci 2008;49:1758-62.
Nagy EV, Toth J, Kaldi I, Damjanovich J, Mezosi E, Lenkey A, et al
. Graves' ophthalmopathy: Eye muscle involvement in patients with diplopia. Eur J Endocrinol 2000;142:591-7.
Träisk F, Tallstedt L, Abraham-Nordling M, Andersson T, Berg G, Calissendorff J, et al
. Thyroid-associated ophthalmopathy after treatment for Graves' hyperthyroidism with antithyroid drugs or iodine-131. J Clin Endocrinol Metab 2009;94:3700-7.
Menconi F, Profilo MA, Leo M, Sisti E, Altea MA, Rocchi R, et al
. Spontaneous improvement of untreated mild Graves' ophthalmopathy: Rundle's curve revisited. Thyroid 2014;24:60-6.
Marcocci C, Kahaly GJ, Krassas GE, Bartalena L, Prummel M, Stahl M, et al
. Selenium and the course of mild Graves' orbitopathy. N
Engl J Med 2011;364:1920-31.
Bartalena L, Pinchera A, Marcocci C. Management of Graves' ophthalmopathy: Reality and perspectives. Endocr Rev 2000;21:168-99.
Eichhorn K, Harrison AR, Bothun ED, McLoon LK, Lee MS. Ocular treatment of thyroid eye disease. Expert Rev Ophthalmol 2010;5:313-25.
Marcocci C, Bartalena L, Tanda ML, Manetti L, Dell'Unto E, Rocchi R, et al
. Comparison of the effectiveness and tolerability of intravenous or oral glucocorticoids associated with orbital radiotherapy in the management of severe Graves' ophthalmopathy: Results of a prospective, single-blind, randomized study. J Clin Endocrinol Metab 2001;86:3562-7.
Macchia PE, Bagattini M, Lupoli G, Vitale M, Vitale G, Fenzi G. High-dose intravenous corticosteroid therapy for Graves' ophthalmopathy. J Endocrinol Invest 2001;24:152-8.
Kauppinen-Mäkelin R, Karma A, Leinonen E, Löyttyniemi E, Salonen O, Sane T, et al
. High dose intravenous methylprednisolone pulse therapy versus oral prednisone for thyroid-associated ophthalmopathy. Acta Ophthalmol Scand 2002;80:316-21.
Kahaly GJ, Pitz S, Hommel G, Dittmar M. Randomized, single blind trial of intravenous versus oral steroid monotherapy in Graves' orbitopathy. J Clin Endocrinol Metab 2005;90:5234-40.
Marcocci C, Bartalena L, Panicucci M, Marconcini C, Cartei F, Cavallacci G, et al
. Orbital cobalt irradiation combined with retrobulbar or systemic corticosteroids for Graves' ophthalmopathy: A comparative study. Clin Endocrinol (Oxf) 1987;27:33-42.
Zang S, Ponto KA, Kahaly GJ. Clinical review: Intravenous glucocorticoids for Graves' orbitopathy: Efficacy and morbidity. J Clin Endocrinol Metab 2011;96:320-32.
Sundar G, Chiam N, Lun K, Koh V. Survey of common practices among oculofacial surgeons in the Asia-Pacific region: Graves' orbitopathy. Orbit 2014;33:319-25.
Bartalena L, Baldeschi L, Dickinson AJ, Eckstein A, Kendall-Taylor P, Marcocci C, et al
. Consensus statement of the European Group On Graves' orbitopathy (EUGOGO) on management of Graves' orbitopathy. Thyroid 2008;18:333-46.
Perumal B, Meyer DR. Treatment of severe thyroid eye disease: A survey of the American Society of Ophthalmic Plastic and Reconstructive Surgery (ASOPRS). Ophthalmic Plast Reconstr Surg 2015;31:127-31.
Bahn R. High-dose intravenous glucocorticoid therapy for Graves' ophthalmopathy: Where are we now? Thyroid 2012;22:1-2.
Zhu W, Ye L, Shen L, Jiao Q, Huang F, Han R, et al
. A prospective, randomized trial of intravenous glucocorticoids therapy with different protocols for patients with Graves' ophthalmopathy. J Clin Endocrinol Metab 2014;99:1999-2007.
Prummel MF, Mourits MP, Berghout A, Krenning EP, van der Gaag R, Koornneef L, et al
. Prednisone and cyclosporine in the treatment of severe Graves' ophthalmopathy. N
Engl J Med 1989;321:1353-9.
Smith JR, Rosenbaum JT. A role for methotrexate in the management of non-infectious orbital inflammatory disease. Br J Ophthalmol 2001;85:1220-4.
Strianese D, Iuliano A, Ferrara M, Comune C, Baronissi I, Napolitano P, D'Alessandro A, Grassi P, Bonavolontà G, Bonavolontà P, Sinisi A, Tranfa F. Methotrexate for the treatment of thyroid eye disease. J Ophthalmol. 2014;2014:128903.
Salvi M, Vannucchi G, Campi I, Rossi S, Bonara P, Sbrozzi F, et al
. Efficacy of rituximab treatment for thyroid-associated ophthalmopathy as a result of intraorbital B-cell depletion in one patient unresponsive to steroid immunosuppression. Eur J Endocrinol 2006;154:511-7.
Bahn RS. Emerging pharmacotherapy for treatment of Graves' disease. Expert Rev Clin Pharmacol 2012;5:605-7.
El Fassi D, Nielsen CH, Kjeldsen J, Clemmensen O, Hegedüs L. Ulcerative colitis following B lymphocyte depletion with rituximab in a patient with Graves' disease. Gut 2008;57:714-5.
El Fassi D, Nielsen CH, Junker P, Hasselbalch HC, Hegedüs L. Systemic adverse events following rituximab therapy in patients with Graves' disease. J Endocrinol Invest 2011;34:e163-7.
Smith TJ. Is there potential for the approval of monoclonal antibodies to treat thyroid-associated ophthalmopathy? Expert Opin Orphan Drugs 2018;6:593-5.
Smith TJ. TSHR as a therapeutic target in Graves' disease. Expert Opin Ther Targets 2017;21:427-32.
Shams PN, Ma R, Pickles T, Rootman J, Dolman PJ. Reduced risk of compressive optic neuropathy using orbital radiotherapy in patients with active thyroid eye disease. Am J Ophthalmol 2014;157:1299-305.
Dolman PJ, Rath S. Orbital radiotherapy for thyroid eye disease. Curr Opin Ophthalmol 2012;23:427-32.
Shorr N, Seiff SR. The four stages of surgical rehabilitation of the patient with dysthyroid ophthalmopathy. Ophthalmology 1986;93:476-83.
Goldberg RA. The evolving paradigm of orbital decompression surgery. Arch Ophthalmol 1998;116:95-6.
Lund VJ, Larkin G, Fells P, Adams G. Orbital decompression for thyroid eye disease: A comparison of external and endoscopic techniques. J Laryngol Otol 1997;111:1051-5.
Sasim IV, de Graaf ME, Berendschot TT, Kalmann R, van Isterdael C, Mourits MP. Coronal or swinging eyelid decompression for patients with disfiguring proptosis in Graves' orbitopathy? Comparison of results in one center. Ophthalmology 2005;112:1310-5.
Goldberg RA, Kim AJ, Kerivan KM. The lacrimal keyhole, orbital door jamb, and basin of the inferior orbital fissure. Three areas of deep bone in the lateral orbit. Arch Ophthalmol 1998;116:1618-24.
Goldberg RA, Perry JD, Hortaleza V, Tong JT. Strabismus after balanced medial plus lateral wall versus lateral wall only orbital decompression for dysthyroid orbitopathy. Ophthalmic Plast Reconstr Surg 2000;16:271-7.
Shorr N, Baylis HI, Goldberg RA, Perry JD. Transcaruncular approach to the medial orbit and orbital apex. Ophthalmology 2000;107:1459-63.
Liao SL, Chang TC, Lin LL. Transcaruncular orbital decompression: An alternate procedure for Graves ophthalmopathy with compressive optic neuropathy. Am J Ophthalmol 2006;141:810-8.
Kim JW, Goldberg RA, Shorr N. The inferomedial orbital strut: An anatomic and radiographic study. Ophthalmic Plast Reconstr Surg 2002;18:355-64.
Bleier BS, Lefebvre DR, Freitag SK. Endoscopic orbital floor decompression with preservation of the inferomedial strut. Int Forum Allergy Rhinol 2014;4:82-4.
Shepard KG, Levin PS, Terris DJ. Balanced orbital decompression for Graves' ophthalmopathy. Laryngoscope 1998;108:1648-53.
Unal M, Leri F, Konuk O, Hasanreisoǧlu B. Balanced orbital decompression combined with fat removal in Graves ophthalmopathy: Do we really need to remove the third wall? Ophthalmic Plast Reconstr Surg 2003;19:112-8.
De Castro DK, Fay A, Wladis EJ, Nguyen J, Osaki T, Metson R, et al
. Self-irrigating piezoelectric device in orbital surgery. Ophthalmic Plast Reconstr Surg 2013;29:118-22.
Krastinova-Lolov D, Bach CA, Hartl DM, Coquille F, Jasinski M, Cecchi P, et al
. Surgical strategy in the treatment of globe protrusion depending on its mechanism (Graves' disease, nonsyndromic exorbitism, or high myopia). Plast Reconstr Surg 2006;117:553-64.
Borumandi F, Hammer B, Kamer L, von Arx G. How predictable is exophthalmos reduction in Graves' orbitopathy? A review of the literature. Br J Ophthalmol 2011;95:1625-30.
Harrad R. Management of strabismus in thyroid eye disease. Eye (Lond) 2015;29:234-7.
Mancini R, Khadavi NM, Goldberg RA. Nonsurgical management of upper eyelid margin asymmetry using hyaluronic acid gel filler. Ophthalmic Plast Reconstr Surg 2011;27:1-3.
Elner VM, Hassan AS, Frueh BR. Graded full-thickness anterior blepharotomy for upper eyelid retraction. Arch Ophthalmol 2004;122:55-60.
Ben Simon GJ, Mansury AM, Schwarcz RM, Modjtahedi S, McCann JD, Goldberg RA. Transconjunctival Müller muscle recession with levator disinsertion for correction of eyelid retraction associated with thyroid-related orbitopathy. Am J Ophthalmol 2005;140:94-9.
Goldberg RA, Lee S, Jayasundera T, Tsirbas A, Douglas RS, McCann JD. Treatment of lower eyelid retraction by expansion of the lower eyelid with hyaluronic Acid gel. Ophthalmic Plast Reconstr Surg 2007;23:343-8.
Hintschich C, Haritoglou C. Full thickness eyelid transsection (blepharotomy) for upper eyelid lengthening in lid retraction associated with Graves' disease. Br J Ophthalmol 2005;89:413-6.
Moran RE. The correction of exophthalmos and levator spasm. Plast Reconstr Surg (1946) 1956;18:411-26.
Putterman AM, Urist M. Surgical treatment of upper eyelid retraction. Arch Ophthalmol 1972;87:401-5.
Kikkawa DO, Pornpanich K, Cruz RC Jr., Levi L, Granet DB. Graded orbital decompression based on severity of proptosis. Ophthalmology 2002;109:1219-24.
Norris JH, Ross JJ, O'Reilly P, Malhotra R. A review of combined orbital decompression and lower eyelid recession surgery for lower eyelid retraction in thyroid orbitopathy. Br J Ophthalmol 2011;95:1664-9.
Lim NC, Amrith S, Sundar G. Pediatric thyroid eye disease–The Singapore experience. Orbit 2014;33:96-103.
Xu N, Cui Y, Xie T, Zheng M. Comparative Efficacy of Medical Treatments for Thyroid Eye Disease: A Network Meta-Analysis. J Ophthalmol. 2018 Dec 12;2018:7184163.
[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]