Curr Treat Options Neurol (2014) 16:303 DOI 10.1007/s11940-014-0303-8
Neurologic Ophthalmology and Otology (RK Shin, Section Editor)
Treatment Options for Thyroid Eye Disease Angelique J. Pillar, MD D. Chimene Richa, MD* Address *Department of Ophthalmology, University of Maryland, 419 West Redwood Street, Suite 420, Baltimore, MD 21201, USA Email: [email protected]
* Springer Science+Business Media New York 2014
This article is part of the Topical Collection on Neurologic Ophthalmology and Otology Keywords Thyroid eye disease I TED I Thyroid-stimulating hormone I TSH I Thyroid-associated ophthalmopathy I Graves’ ophthalmopathy I Compressive optic neuropathy I Exophthalmos I Eyelid retraction I Proptosis
Opinion statement Patients with thyroid eye disease (TED) experience hypertrophy of their extraocular muscles and an increase in intraorbital fat volume leading to eyelid retraction, proptosis, double vision, and optic nerve compression. These orbital changes are thought to be due to a cross-reaction of thyroid stimulating hormone (TSH) with antigens in the orbit. Therefore, the key to treatment is achievement of a euthyroid state in patients with abnormal thyroid function. Cigarette smoking is the strongest modifiable risk factor linked with progression and poor response to treatment. All TED patients should be counseled and offered help with smoking cessation. The treatment of TED symptoms must be customized to each patient, as the degree of orbital involvement can vary. During the active state, evaluation of sight-threatening compressive optic neuropathy and treatment of corneal exposure by an ophthalmologist is crucial to avoid irreversible damage. In most patients, local therapy with artificial tears, gels, and ointments can offer symptomatic relief of irritation and dryness. In addition, antioxidant therapy with selenium has been shown to improve quality of life in patients with mild orbital involvement. Some patients will require systemic oral or IV steroids at the onset of an active inflammatory state. However, approximately one third of patients will not be responsive to steroid therapy alone. In these patients, the addition of orbital radiation or use of immune modulation has shown value. Orbital decompression surgery should be considered for cases of vision-threatening optic neuropathy despite maximal medical therapy. Approximately 3–6 months after cessation of the active state and stabilization of symptoms, rehabilitative treatment may be offered. Treatment is offered in a 3-stage surgical approach with orbital decompression surgery, followed by strabismus surgery for any resultant binocular diplopia, and finally eyelid surgery to address eyelid retraction. Meanwhile, symptomatic diplopia may be addressed with monocular patching or prisms.
303, Page 2 of 8
Curr Treat Options Neurol (2014) 16:303
Introduction Thyroid eye disease (TED) is an autoimmune condition characterized by inflammation of the orbital tissue thought to be due to deranged activation of thyroid-stimulating hormone receptor expressed on orbital fibroblasts by thyrotropin receptor antibodies. Subsequent activation of cytokines, including interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and interleukin-1α (IL-1α), leads to expansion of the orbit via deposition of hyaluronan, a hydrophilic extracellular matrix component. Meanwhile, stimulation of insulin-like growth factor receptors (IGF-1R) leads to infiltration and activation of T lymphocytes and B lymphocytes, which leads to further production of cytokines. T lymphocytes also produce proadipogenic prostaglandins, which cause fibroblasts to differentiate into mature fat cells. Together, this cascade of molecular changes leads to the classic findings of TED: extraocular muscle hypertrophy with widely spaced muscle fibers surrounded by deposition of collagen and hyaluron as well as orbital fat deposition. TED may be referred to as Graves’ ophthalmopathy, Graves' orbitopathy, thyroid-associated ophthalmopathy, or thyroid orbitopathy, and may be one of the presenting diagnostic signs of thyroid dysfunction. Although most often seen in association with hyperthyroidism, as with Graves’ disease, TED is also s e e n i n p a t i e n t s wi t h h y p o thy r o i d i s m d u e t o Hashimoto's thyroiditis and in a small number of euthyroid patients [1]. The annual adjusted incidence range is approximately 16 per 100,000 women and 3 per 100,000 men with a female predominance of 4:1 [2]. Diagnosis is made clinically with the presence of eyelid retraction, lid lag, and variable proptosis accompanied
by eyelid edema, conjunctival edema (chemosis), exposure keratopathy, and diplopia attributable to strabismus. Patients may complain of orbital pain, redness, or swelling of the eyelids and conjunctiva, change in appearance, double vision, or decreased visual acuity. Approximately one-half of patients with Graves’ hyperthyroidism report symptoms, which may be bilateral but are often asymmetric; unilateral symptoms are less common. Imaging studies, including orbital computed tomography (CT) scanning, magnetic resonance imaging (MRI), or orbital ultrasound, may aid in the diagnosis and show typical findings of extra-ocular muscle enlargement with tendon-sparing, orbital fat expansion, and proptosis. The course in TED is variable but is characterized by a self-limited active phase lasting approximately 1.5– 3 years followed by a stable inactive/static phase; in rare cases, the course follows a cycle of exacerbations and remissions. Activity may be graded with the help of a clinical activity score (CAS), a 10-point system that also predicts response to anti-inflammatory therapies. An additional classification system with accompanying online clinical atlas has been made available by the European Group of Graves’ Orbitopathy (EUGOGO) with specific severity grading metrics. Overall, approximately 3 %–5 % of patients with TED will suffer from acute vision-threatening symptoms. Patients with active disease should be watched closely for signs of compressive optic neuropathy. This can be diagnosed with testing of visual acuity, color vision, and automated visual field testing; physical examination can show a relative afferent pupillary defect and progression on Hertel exophthalmometry. These cases should be referred urgently for subspecialist evaluation and treatment.
Treatment summary &
&
Establishment of a euthyroid state is crucial in controlling TED. Systemic management by an endocrinologist may include antithyroid medication, radioactive iodine, or thyroid surgery. Radioactive iodine treatment may lead to worsening TED, presumably due to thyroid antigen leakage with augmented TSH-R antibody production. Prophylactic corticosteroids or treatment of progression with steroids may be indicated. Initial treatment for TED must be customized to the level of orbital involvement (Table 1, Fig. 1). Management of local mild symptoms begins with artificial tears; recent evidence shows that selenium supplementation
Curr Treat Options Neurol (2014) 16:303
Page 3 of 8, 303
Table 1. Summary of pharmaceutical therapies for thyroid eye disease Treatment
Regimen
Mechanism
Therapeutic phase
Artificial tears (preservative-free) Selenium
1 drop both eyes 4–6 times per d
Surface lubrication
100 mcg twice daily×6 mo
Antioxidant
Oral steroids (prednisone) Local orbital steroids (triamcinolone) Intravenous steroids (methylprednisolone)
40–100 mg/day then 10 mg/wk taper
Immune suppression
20 mg (0.5 mL of 40 mg/mL) peribulbar injection or subconjunctival eyelid injection 500 mg IV/wk×6 wk then 250 mg IV/wk× 6 weeks; 500 mg IV daily×3 consecutive d followed by PO taper for compressive optic neuropathy 20 Gy in 10 fractions over 2 wk±concurrent corticosteroids Two 1-g infusions 2 wk apart
Immune suppression
Mild to moderate Mild to moderate Moderate to severe Moderate to severe Severe or acute phase
External orbital radiation Rituximab (Anti- CD-20) Tocilizumab (Anti- IL-6)
4–8 mg/kg every 4 wk
Methotrexate
7.5–10 mg weekly
& & &
Immune suppression
Destruction of orbital lymphocytes Depletes B cells and may interfere with antigen presentation to T-cells Reduces IL-6, a proinflammatory cytokine Anti-metabolite
Severe or acute phase Severe or acute phase Severe or acute phase Severe or acute phase
for 6 months may slow progression of the disease in some cases. Corticosteroids are used to treat the acute phase especially in patients with increasing proptosis or diplopia and in patients at risk of developing an optic neuropathy. For patients who develop signs of optic neuropathy, immediate intravenous glucocorticoid administration with orbital decompression surgery can be sight saving. New evidence shows the benefit of immunosuppressive biologic agents for refractory cases nonresponsive to corticosteroids.
Diet and lifestyle &
All TED patients should be counseled to quit smoking as current smokers are more likely to experience disease progression and worse treatment outcome in a dose dependent manner [3, Class III].
Pharmacologic treatment Artificial tears (preservative-free) Standard dosage
One drop to each eye four to six times per day.
303, Page 4 of 8
Curr Treat Options Neurol (2014) 16:303
Fig. 1. Treatment flow diagram for thyroid eye disease Contraindications
None.
Main drug interactions
None.
Main side effects
None.
Special points Cost
Serves to lubricate the corneal surface and conjunctiva. Avoid using within 5 min of other medicated eye drops [4, Class IV]. Approximately $5 to $15 per ounce.
Curr Treat Options Neurol (2014) 16:303
Page 5 of 8, 303
Selenium (sodium selenite) Standard dosage Contraindications
100 mcg twice daily for 6 months. None.
Main drug interactions
Selenium may slow clotting and should be used in caution with anticoagulants and anti-platelet agents.
Main side effects
Higher doses can cause gastrointestinal upset, nail changes, loss of energy, and irritability.
Special points
Cost
Selenium is an antioxidant thought to neutralize oxygen free radicals which play a role in TED pathogenesis. A randomized, double-blind, placebocontrolled trial showed that selenium significantly improved quality of life, reduced ocular involvement, and slowed progression of the disease in patients with mild Graves' orbitopathy [5•, Class I]. Approximately $5–$10 for 100 100-mcg tablets.
Steroids (oral prednisone or intravenous methylprednisolone) Standard dosage
For soft tissue inflammation or diplopia, prednisone 40–100 mg/day orally followed by a 10 mg/week taper. Or, methylprednisolone 500 mg IV per week×6 weeks followed by 250 mg IV per week (pulse therapy)×6 weeks. For compressive optic neuropathy, methylprednisolone 500 mg IV daily×3 consecutive days followed by prednisone taper.
Contraindications
Corticosteroids should be used with caution in patients with diabetes mellitus or hypertension. Also, steroids should be avoided in patients with fungal or mycobacterial infections.
Main drug interactions
May increase or decrease the effects of warfarin; levels should be monitored closely. Nonsteroidal anti-inflammatory drugs and COX-2 inhibitors can increase the risk of gastrointestinal bleeding.
Main side effects
Hyperglycemia, hypertension, myalgias, gastrointestinal upset, palpitations, weight gain, osteoporosis, psychosocial disturbances, aseptic necrosis of the femoral head, pancreatitis, delayed wound healing.
Special points
Corticosteroids serve as powerful anti-inflammatory agents via immune suppression. A prospective randomized controlled trial showed a weekly protocol of IV methylprednisolone therapy is more efficient and safer than the daily protocol in patients with severe or active disease [6, Class I].
Cost
100 20-mg tablets cost approximately $8.00. 5 mL of methylprednisolone acetate suspension (80 mg/mL) costs about $80.
Interventional procedures Local corticosteroids injections (peribulbar or subconjunctival triamcinolone) Standard procedure
4 weekly peribulbar injections of triamcinolone 20 mg (0.5 mL of 40 mg/mL) injected to the inferolateral orbital quadrant. Alternatively, one to three
303, Page 6 of 8
Curr Treat Options Neurol (2014) 16:303 subconjunctival eyelid injections of triamcinolone 20 mg (0.5 mL of 40 mg/mL) 3 weeks apart. Contraindications
Glaucoma or ocular hypertension.
Complications
Elevated intraocular pressure.
Special points
A randomized control study showed that four weekly peribulbar injections of triamcinolone reduced diplopia and decreased size of extraocular muscles in patients diagnosed with TED G6 months [7, Class I]. A prospective single blind randomized clinical trial showed subconjunctival triamcinolone improved recent onset mild eyelid swelling and retraction [8, Class II].
Cost
Approximately $10–$20 for 0.5 cc of triamcinolone 40/mg/mL.
Orbital radiation therapy Standard procedure
20 Gy cumulative dose of external beam radiation administered in 10 doses over 2 weeks.
Contraindications
Diabetes mellitus is a relative contraindication due to the increased risk of progression of retinopathy. Use in caution in those G35 years old due to carcinogenic potential.
Complications
Cataracts, retinopathy (1 %–2 %/10 years, 21 %/20 years), transient blindness, concern for secondary malignancy.
Special points
Radiotherapy suppresses fibroblasts and decreases orbital lymphocyte cytokine production. Radiotherapy is not routinely indicated in managing mild to moderate TED, as proptosis, eyelid retraction, and soft tissue changes do not improve [9, Class I]. However, a recent case control retrospective study showed improved rate of compressive optic neuropathy and greater ocular motility in patients receiving orbital radiotherapy in addition to corticosteroids compared with corticosteroids alone [10, Class III].
Cost
Total cost is approximately $15,000 to greater than $25,000.
Emerging therapies Rituximab Standard procedure
Two 1-g infusions of Rituximab, 2 weeks apart, with premedication 30 min prior to infusion using 100 mg IV methylprednisolone, 1 g oral acetaminophen, and 50 mg oral diphenhydramine.
Contraindications
Chronic hepatitis B infection, severe active infections (cytomegalovirus herpes simplex virus, varicella zoster virus, West Nile virus), history of cardiac arrhythmias, a history of progressive multifocal leukoencephalopathy (PML).
Complications
Infusion reaction, hepatitis B reactivation and fulminant hepatitis, PML, leukopenia, neutropenia, thrombocytopenia, nausea, vomiting, pruritus, weakness, headache, rhinitis.
Special points
Rituximab is a mouse-human monoclonal antibody that targets CD20 on immature and mature B cells. Its mechanism of action is thought to en-
Curr Treat Options Neurol (2014) 16:303
Page 7 of 8, 303 hancement of apoptosis, leading to B-cell depletion. Recent non-randomized cohort studies report improvement of proptosis and eye motility in severe or steroid-resistant cases [11, Class IV]. Small case series demonstrated reduction of clinical activity after intraorbital injection [12, Class IV]. Controlled studies are currently pending.
Cost
Total cost is approximately $12,570 for the medication, infusion, and monitoring labs and is not routinely covered by insurance.
Tocilizumab (monoclonal antibody against IL-6) Standard procedure Contraindications
4–8 mg/kg every 4 weeks. Concurrent serious infections.
Complications
Fatigue, myalgia, neutropenia, digestive discomfort, pruritis, tinnitus, arthralgias.
Special points
Tocilizumab is a humanized monoclonal antibody against interleukin-6 receptor which has been shown in a prospective interventional nonrandomized study to reduce clinical activity in patients with TED refractory to IV steroids [13, Class III].
Cost
Approximately $1,060 to $2,125 per month.
Methotrexate Standard procedure Contraindications
7.5 mg orally weekly in divided doses G60 kg and 10 mg 960 kg. Pregnancy, alcoholism, liver disease, immunodeficiencies, blood dyscrasias.
Complications
Nausea, vomiting, abnormal liver function tests, mouth sores, shortness of breath, persistent cough.
Special points
Methotrexate is an anti-metabolite thought to work on TED via its antiproliferative and anti-inflammatory effects. A retrospective comparative case series demonstrated improvement in clinical activity and motility disturbances, however no effect on visual acuity, exophthalmos, or eyelid retraction in patients with reactivation of TED following discontinuation of steroids due to side effects [14, Class IV].
Cost
Approximately $18 for 30 2.5-mg tablets.
Compliance with Ethics Guidelines Conflict of Interest Angelique J. Pillar and D. Chimene Richa declare that they have no conflicts of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
303, Page 8 of 8
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References and Recommended Reading Papers of particular interest, published recently have been highlighted as: • Of importance 1.
Bahn RS. Graves’ ophthalmopathy. N Engl J Med. 2010;362:726–38. 2. Wiersinga WM, Bartalena L. Epidemiology and prevention of Graves’ ophthalmopathy. Thyroid. 2002;12:855–60. 3. Thornton J, Kelly SP, Harrison RA, Edwards R. Cigarette smoking and thyroid eye disease: a systematic review. Eye. 2007;21:1135–45. 4. Phillips ME, Marzban MM, Kathuria SS. Treatment of thyroid eye disease. Curr Treat Options Neurol. 2010;12(1):64–9. 5.• Marcocci C, Kahaly GJ, Krassas GE, et al. Selenium and the course of mild Graves’ orbitopathy. N Engl J Med. 2011;364:1920–31. This is an important study that demonstrates the benefit of selenium supplementation on mild thyroid eye disease 6. Kahaly GJ, Pitz S, Hommel G, et al. Randomized, single blind trial of intravenous versus oral steroid monotherapy in Graves’ orbitopathy. J Clin Endocrinol Metab. 2005;90:5234–40. 7. Ebner R. Treatment of thyroid associated ophthalmopathy with periocular injections of triamcinolone. Br J Ophthalmol. 2004;88(11):1380–6. 8. Lee SJ, Rim TH, Jang SY, Kim CY, Shin DY, Lee EJ, et al. Treatment of upper eyelid retraction related to thyroid-associated ophthalmopathy using
9.
10.
11.
12.
13.
14.
subconjunctival triamcinolone injections. Graefes Arch Clin Exp Ophthalmol. 2013;251(1):261–70. Gorman CA, Garrity JA, Fatourechi V, et al. A prospective, randomized, double-blind, placebo-controlled study of orbital radiotherapy for Graves’ ophthalmopathy. Ophthalmology. 2001;108:1523–34. 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(6):1299–305. Salvi M, Vannucchi G, Beck-Peccoz P. Potential utility of rituximab for Graves' orbitopathy. J Clin Endocrinol Metab. 2013;98(11):4291–9. Savino G, Balia L, Colucci D, Battendieri R, Gari M, Corsello SM, et al. Intraorbital injection of rituximab: a new approach for active thyroid-associated orbitopathy, a prospective case series. Minerva Endocrinol. 2013;38(2):173–9. Pérez-Moreiras JV, Alvarez-López A, Gómez EC. Treatment of active corticosteroid-resistant graves' orbitopathy. Ophthal Plast Reconstr Surg. 2014;30(2):162–7. Strianese D, Iuliano A, Ferrara M, Comune C, Baronissi I, Napolitano P, et al. Methotrexate for the treatment of thyroid eye disease. J Ophthalmol. 2014;2014:128903.
Neurologic Ophthalmology and Otology (RK Shin, Section Editor)
Treatment Options for Thyroid Eye Disease Angelique J. Pillar, MD D. Chimene Richa, MD* Address *Department of Ophthalmology, University of Maryland, 419 West Redwood Street, Suite 420, Baltimore, MD 21201, USA Email: [email protected]
* Springer Science+Business Media New York 2014
This article is part of the Topical Collection on Neurologic Ophthalmology and Otology Keywords Thyroid eye disease I TED I Thyroid-stimulating hormone I TSH I Thyroid-associated ophthalmopathy I Graves’ ophthalmopathy I Compressive optic neuropathy I Exophthalmos I Eyelid retraction I Proptosis
Opinion statement Patients with thyroid eye disease (TED) experience hypertrophy of their extraocular muscles and an increase in intraorbital fat volume leading to eyelid retraction, proptosis, double vision, and optic nerve compression. These orbital changes are thought to be due to a cross-reaction of thyroid stimulating hormone (TSH) with antigens in the orbit. Therefore, the key to treatment is achievement of a euthyroid state in patients with abnormal thyroid function. Cigarette smoking is the strongest modifiable risk factor linked with progression and poor response to treatment. All TED patients should be counseled and offered help with smoking cessation. The treatment of TED symptoms must be customized to each patient, as the degree of orbital involvement can vary. During the active state, evaluation of sight-threatening compressive optic neuropathy and treatment of corneal exposure by an ophthalmologist is crucial to avoid irreversible damage. In most patients, local therapy with artificial tears, gels, and ointments can offer symptomatic relief of irritation and dryness. In addition, antioxidant therapy with selenium has been shown to improve quality of life in patients with mild orbital involvement. Some patients will require systemic oral or IV steroids at the onset of an active inflammatory state. However, approximately one third of patients will not be responsive to steroid therapy alone. In these patients, the addition of orbital radiation or use of immune modulation has shown value. Orbital decompression surgery should be considered for cases of vision-threatening optic neuropathy despite maximal medical therapy. Approximately 3–6 months after cessation of the active state and stabilization of symptoms, rehabilitative treatment may be offered. Treatment is offered in a 3-stage surgical approach with orbital decompression surgery, followed by strabismus surgery for any resultant binocular diplopia, and finally eyelid surgery to address eyelid retraction. Meanwhile, symptomatic diplopia may be addressed with monocular patching or prisms.
303, Page 2 of 8
Curr Treat Options Neurol (2014) 16:303
Introduction Thyroid eye disease (TED) is an autoimmune condition characterized by inflammation of the orbital tissue thought to be due to deranged activation of thyroid-stimulating hormone receptor expressed on orbital fibroblasts by thyrotropin receptor antibodies. Subsequent activation of cytokines, including interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and interleukin-1α (IL-1α), leads to expansion of the orbit via deposition of hyaluronan, a hydrophilic extracellular matrix component. Meanwhile, stimulation of insulin-like growth factor receptors (IGF-1R) leads to infiltration and activation of T lymphocytes and B lymphocytes, which leads to further production of cytokines. T lymphocytes also produce proadipogenic prostaglandins, which cause fibroblasts to differentiate into mature fat cells. Together, this cascade of molecular changes leads to the classic findings of TED: extraocular muscle hypertrophy with widely spaced muscle fibers surrounded by deposition of collagen and hyaluron as well as orbital fat deposition. TED may be referred to as Graves’ ophthalmopathy, Graves' orbitopathy, thyroid-associated ophthalmopathy, or thyroid orbitopathy, and may be one of the presenting diagnostic signs of thyroid dysfunction. Although most often seen in association with hyperthyroidism, as with Graves’ disease, TED is also s e e n i n p a t i e n t s wi t h h y p o thy r o i d i s m d u e t o Hashimoto's thyroiditis and in a small number of euthyroid patients [1]. The annual adjusted incidence range is approximately 16 per 100,000 women and 3 per 100,000 men with a female predominance of 4:1 [2]. Diagnosis is made clinically with the presence of eyelid retraction, lid lag, and variable proptosis accompanied
by eyelid edema, conjunctival edema (chemosis), exposure keratopathy, and diplopia attributable to strabismus. Patients may complain of orbital pain, redness, or swelling of the eyelids and conjunctiva, change in appearance, double vision, or decreased visual acuity. Approximately one-half of patients with Graves’ hyperthyroidism report symptoms, which may be bilateral but are often asymmetric; unilateral symptoms are less common. Imaging studies, including orbital computed tomography (CT) scanning, magnetic resonance imaging (MRI), or orbital ultrasound, may aid in the diagnosis and show typical findings of extra-ocular muscle enlargement with tendon-sparing, orbital fat expansion, and proptosis. The course in TED is variable but is characterized by a self-limited active phase lasting approximately 1.5– 3 years followed by a stable inactive/static phase; in rare cases, the course follows a cycle of exacerbations and remissions. Activity may be graded with the help of a clinical activity score (CAS), a 10-point system that also predicts response to anti-inflammatory therapies. An additional classification system with accompanying online clinical atlas has been made available by the European Group of Graves’ Orbitopathy (EUGOGO) with specific severity grading metrics. Overall, approximately 3 %–5 % of patients with TED will suffer from acute vision-threatening symptoms. Patients with active disease should be watched closely for signs of compressive optic neuropathy. This can be diagnosed with testing of visual acuity, color vision, and automated visual field testing; physical examination can show a relative afferent pupillary defect and progression on Hertel exophthalmometry. These cases should be referred urgently for subspecialist evaluation and treatment.
Treatment summary &
&
Establishment of a euthyroid state is crucial in controlling TED. Systemic management by an endocrinologist may include antithyroid medication, radioactive iodine, or thyroid surgery. Radioactive iodine treatment may lead to worsening TED, presumably due to thyroid antigen leakage with augmented TSH-R antibody production. Prophylactic corticosteroids or treatment of progression with steroids may be indicated. Initial treatment for TED must be customized to the level of orbital involvement (Table 1, Fig. 1). Management of local mild symptoms begins with artificial tears; recent evidence shows that selenium supplementation
Curr Treat Options Neurol (2014) 16:303
Page 3 of 8, 303
Table 1. Summary of pharmaceutical therapies for thyroid eye disease Treatment
Regimen
Mechanism
Therapeutic phase
Artificial tears (preservative-free) Selenium
1 drop both eyes 4–6 times per d
Surface lubrication
100 mcg twice daily×6 mo
Antioxidant
Oral steroids (prednisone) Local orbital steroids (triamcinolone) Intravenous steroids (methylprednisolone)
40–100 mg/day then 10 mg/wk taper
Immune suppression
20 mg (0.5 mL of 40 mg/mL) peribulbar injection or subconjunctival eyelid injection 500 mg IV/wk×6 wk then 250 mg IV/wk× 6 weeks; 500 mg IV daily×3 consecutive d followed by PO taper for compressive optic neuropathy 20 Gy in 10 fractions over 2 wk±concurrent corticosteroids Two 1-g infusions 2 wk apart
Immune suppression
Mild to moderate Mild to moderate Moderate to severe Moderate to severe Severe or acute phase
External orbital radiation Rituximab (Anti- CD-20) Tocilizumab (Anti- IL-6)
4–8 mg/kg every 4 wk
Methotrexate
7.5–10 mg weekly
& & &
Immune suppression
Destruction of orbital lymphocytes Depletes B cells and may interfere with antigen presentation to T-cells Reduces IL-6, a proinflammatory cytokine Anti-metabolite
Severe or acute phase Severe or acute phase Severe or acute phase Severe or acute phase
for 6 months may slow progression of the disease in some cases. Corticosteroids are used to treat the acute phase especially in patients with increasing proptosis or diplopia and in patients at risk of developing an optic neuropathy. For patients who develop signs of optic neuropathy, immediate intravenous glucocorticoid administration with orbital decompression surgery can be sight saving. New evidence shows the benefit of immunosuppressive biologic agents for refractory cases nonresponsive to corticosteroids.
Diet and lifestyle &
All TED patients should be counseled to quit smoking as current smokers are more likely to experience disease progression and worse treatment outcome in a dose dependent manner [3, Class III].
Pharmacologic treatment Artificial tears (preservative-free) Standard dosage
One drop to each eye four to six times per day.
303, Page 4 of 8
Curr Treat Options Neurol (2014) 16:303
Fig. 1. Treatment flow diagram for thyroid eye disease Contraindications
None.
Main drug interactions
None.
Main side effects
None.
Special points Cost
Serves to lubricate the corneal surface and conjunctiva. Avoid using within 5 min of other medicated eye drops [4, Class IV]. Approximately $5 to $15 per ounce.
Curr Treat Options Neurol (2014) 16:303
Page 5 of 8, 303
Selenium (sodium selenite) Standard dosage Contraindications
100 mcg twice daily for 6 months. None.
Main drug interactions
Selenium may slow clotting and should be used in caution with anticoagulants and anti-platelet agents.
Main side effects
Higher doses can cause gastrointestinal upset, nail changes, loss of energy, and irritability.
Special points
Cost
Selenium is an antioxidant thought to neutralize oxygen free radicals which play a role in TED pathogenesis. A randomized, double-blind, placebocontrolled trial showed that selenium significantly improved quality of life, reduced ocular involvement, and slowed progression of the disease in patients with mild Graves' orbitopathy [5•, Class I]. Approximately $5–$10 for 100 100-mcg tablets.
Steroids (oral prednisone or intravenous methylprednisolone) Standard dosage
For soft tissue inflammation or diplopia, prednisone 40–100 mg/day orally followed by a 10 mg/week taper. Or, methylprednisolone 500 mg IV per week×6 weeks followed by 250 mg IV per week (pulse therapy)×6 weeks. For compressive optic neuropathy, methylprednisolone 500 mg IV daily×3 consecutive days followed by prednisone taper.
Contraindications
Corticosteroids should be used with caution in patients with diabetes mellitus or hypertension. Also, steroids should be avoided in patients with fungal or mycobacterial infections.
Main drug interactions
May increase or decrease the effects of warfarin; levels should be monitored closely. Nonsteroidal anti-inflammatory drugs and COX-2 inhibitors can increase the risk of gastrointestinal bleeding.
Main side effects
Hyperglycemia, hypertension, myalgias, gastrointestinal upset, palpitations, weight gain, osteoporosis, psychosocial disturbances, aseptic necrosis of the femoral head, pancreatitis, delayed wound healing.
Special points
Corticosteroids serve as powerful anti-inflammatory agents via immune suppression. A prospective randomized controlled trial showed a weekly protocol of IV methylprednisolone therapy is more efficient and safer than the daily protocol in patients with severe or active disease [6, Class I].
Cost
100 20-mg tablets cost approximately $8.00. 5 mL of methylprednisolone acetate suspension (80 mg/mL) costs about $80.
Interventional procedures Local corticosteroids injections (peribulbar or subconjunctival triamcinolone) Standard procedure
4 weekly peribulbar injections of triamcinolone 20 mg (0.5 mL of 40 mg/mL) injected to the inferolateral orbital quadrant. Alternatively, one to three
303, Page 6 of 8
Curr Treat Options Neurol (2014) 16:303 subconjunctival eyelid injections of triamcinolone 20 mg (0.5 mL of 40 mg/mL) 3 weeks apart. Contraindications
Glaucoma or ocular hypertension.
Complications
Elevated intraocular pressure.
Special points
A randomized control study showed that four weekly peribulbar injections of triamcinolone reduced diplopia and decreased size of extraocular muscles in patients diagnosed with TED G6 months [7, Class I]. A prospective single blind randomized clinical trial showed subconjunctival triamcinolone improved recent onset mild eyelid swelling and retraction [8, Class II].
Cost
Approximately $10–$20 for 0.5 cc of triamcinolone 40/mg/mL.
Orbital radiation therapy Standard procedure
20 Gy cumulative dose of external beam radiation administered in 10 doses over 2 weeks.
Contraindications
Diabetes mellitus is a relative contraindication due to the increased risk of progression of retinopathy. Use in caution in those G35 years old due to carcinogenic potential.
Complications
Cataracts, retinopathy (1 %–2 %/10 years, 21 %/20 years), transient blindness, concern for secondary malignancy.
Special points
Radiotherapy suppresses fibroblasts and decreases orbital lymphocyte cytokine production. Radiotherapy is not routinely indicated in managing mild to moderate TED, as proptosis, eyelid retraction, and soft tissue changes do not improve [9, Class I]. However, a recent case control retrospective study showed improved rate of compressive optic neuropathy and greater ocular motility in patients receiving orbital radiotherapy in addition to corticosteroids compared with corticosteroids alone [10, Class III].
Cost
Total cost is approximately $15,000 to greater than $25,000.
Emerging therapies Rituximab Standard procedure
Two 1-g infusions of Rituximab, 2 weeks apart, with premedication 30 min prior to infusion using 100 mg IV methylprednisolone, 1 g oral acetaminophen, and 50 mg oral diphenhydramine.
Contraindications
Chronic hepatitis B infection, severe active infections (cytomegalovirus herpes simplex virus, varicella zoster virus, West Nile virus), history of cardiac arrhythmias, a history of progressive multifocal leukoencephalopathy (PML).
Complications
Infusion reaction, hepatitis B reactivation and fulminant hepatitis, PML, leukopenia, neutropenia, thrombocytopenia, nausea, vomiting, pruritus, weakness, headache, rhinitis.
Special points
Rituximab is a mouse-human monoclonal antibody that targets CD20 on immature and mature B cells. Its mechanism of action is thought to en-
Curr Treat Options Neurol (2014) 16:303
Page 7 of 8, 303 hancement of apoptosis, leading to B-cell depletion. Recent non-randomized cohort studies report improvement of proptosis and eye motility in severe or steroid-resistant cases [11, Class IV]. Small case series demonstrated reduction of clinical activity after intraorbital injection [12, Class IV]. Controlled studies are currently pending.
Cost
Total cost is approximately $12,570 for the medication, infusion, and monitoring labs and is not routinely covered by insurance.
Tocilizumab (monoclonal antibody against IL-6) Standard procedure Contraindications
4–8 mg/kg every 4 weeks. Concurrent serious infections.
Complications
Fatigue, myalgia, neutropenia, digestive discomfort, pruritis, tinnitus, arthralgias.
Special points
Tocilizumab is a humanized monoclonal antibody against interleukin-6 receptor which has been shown in a prospective interventional nonrandomized study to reduce clinical activity in patients with TED refractory to IV steroids [13, Class III].
Cost
Approximately $1,060 to $2,125 per month.
Methotrexate Standard procedure Contraindications
7.5 mg orally weekly in divided doses G60 kg and 10 mg 960 kg. Pregnancy, alcoholism, liver disease, immunodeficiencies, blood dyscrasias.
Complications
Nausea, vomiting, abnormal liver function tests, mouth sores, shortness of breath, persistent cough.
Special points
Methotrexate is an anti-metabolite thought to work on TED via its antiproliferative and anti-inflammatory effects. A retrospective comparative case series demonstrated improvement in clinical activity and motility disturbances, however no effect on visual acuity, exophthalmos, or eyelid retraction in patients with reactivation of TED following discontinuation of steroids due to side effects [14, Class IV].
Cost
Approximately $18 for 30 2.5-mg tablets.
Compliance with Ethics Guidelines Conflict of Interest Angelique J. Pillar and D. Chimene Richa declare that they have no conflicts of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
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References and Recommended Reading Papers of particular interest, published recently have been highlighted as: • Of importance 1.
Bahn RS. Graves’ ophthalmopathy. N Engl J Med. 2010;362:726–38. 2. Wiersinga WM, Bartalena L. Epidemiology and prevention of Graves’ ophthalmopathy. Thyroid. 2002;12:855–60. 3. Thornton J, Kelly SP, Harrison RA, Edwards R. Cigarette smoking and thyroid eye disease: a systematic review. Eye. 2007;21:1135–45. 4. Phillips ME, Marzban MM, Kathuria SS. Treatment of thyroid eye disease. Curr Treat Options Neurol. 2010;12(1):64–9. 5.• Marcocci C, Kahaly GJ, Krassas GE, et al. Selenium and the course of mild Graves’ orbitopathy. N Engl J Med. 2011;364:1920–31. This is an important study that demonstrates the benefit of selenium supplementation on mild thyroid eye disease 6. Kahaly GJ, Pitz S, Hommel G, et al. Randomized, single blind trial of intravenous versus oral steroid monotherapy in Graves’ orbitopathy. J Clin Endocrinol Metab. 2005;90:5234–40. 7. Ebner R. Treatment of thyroid associated ophthalmopathy with periocular injections of triamcinolone. Br J Ophthalmol. 2004;88(11):1380–6. 8. Lee SJ, Rim TH, Jang SY, Kim CY, Shin DY, Lee EJ, et al. Treatment of upper eyelid retraction related to thyroid-associated ophthalmopathy using
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subconjunctival triamcinolone injections. Graefes Arch Clin Exp Ophthalmol. 2013;251(1):261–70. Gorman CA, Garrity JA, Fatourechi V, et al. A prospective, randomized, double-blind, placebo-controlled study of orbital radiotherapy for Graves’ ophthalmopathy. Ophthalmology. 2001;108:1523–34. 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(6):1299–305. Salvi M, Vannucchi G, Beck-Peccoz P. Potential utility of rituximab for Graves' orbitopathy. J Clin Endocrinol Metab. 2013;98(11):4291–9. Savino G, Balia L, Colucci D, Battendieri R, Gari M, Corsello SM, et al. Intraorbital injection of rituximab: a new approach for active thyroid-associated orbitopathy, a prospective case series. Minerva Endocrinol. 2013;38(2):173–9. Pérez-Moreiras JV, Alvarez-López A, Gómez EC. Treatment of active corticosteroid-resistant graves' orbitopathy. Ophthal Plast Reconstr Surg. 2014;30(2):162–7. Strianese D, Iuliano A, Ferrara M, Comune C, Baronissi I, Napolitano P, et al. Methotrexate for the treatment of thyroid eye disease. J Ophthalmol. 2014;2014:128903.
