Thyroid Eye Disease

Abstract

Thyroid eye disease, although rare, is the most common inflammatory orbital disorder and is associated with autoimmune thyroid dysfunction. It is a progressive disorder with symptoms and signs that may cause significant facial disfigurement, visual disability, but rarely blindness. We will review the diagnostic criteria, immunologic basis, clinical course, and medical and surgical treatments for thyroid eye disease. Recent developments in the use of biologic agents to treat this disorder appear to be changing its progression curve and offer the first specific and preventative therapeutic options.

Definition and Diagnostic Criteria

Thyroid eye disease (TED) is an autoimmune inflammatory disorder of the orbit that may cause considerable ocular morbidity. A diagnosis of TED is made by either of the following two criteria outlined by Bartley.¹ When eyelid retraction is evident, the additional presence of abnormal thyroid function or regulation, exophthalmos, optic nerve dysfunction, or extraocular muscle (EOM) involvement provides the diagnosis, after excluding confounding causes. If eyelid retraction is absent, then diagnosis is made via exophthalmos, optic nerve dysfunction, or EOM involvement in the setting of abnormal thyroid function or regulation. In about 90% of cases, TED is associated with Graves’ disease, requiring multi-specialty collaboration between ophthalmology, endocrinology, and otolaryngology.

Pathophysiology and Epidemiology

TED is characterized by orbital inflammation due to fibroblast activation.² Historically, numerous pathogenic models have been proposed, but more recent study has demonstrated the importance of orbital CD34+ fibroblasts.³ In response to molecular signaling, these fibroblasts differentiate into adipocytes and myofibroblasts. The CD34+ fibroblasts express thyroglobulin, thyroid-stimulating hormone (TSH), and other thyroid-related peptides. These signal molecules stimulate the TSH receptor and insulin-like growth factor I (IGF-1) complex, cascading to adipogenesis and fibroblast hyaluronic acid synthesis within the orbit.³ Increased orbital adipose tissue and glycosaminoglycan sequestration within EOMs leads to soft tissue volume expansion, resulting in increased intraorbital congestion and pressure causing the pathogenic findings in TED.

The incidence of TED favors a female preponderance, with 16 cases per 100,000 females, compared to 2.9 cases per 100,000 males.⁴ Interestingly, severe TED is more common in males, 4:1⁵ Additionally, males tend to have presentations later in life.⁶ In the pediatric population, the incidence is 1.7–3.5 cases per 100,000 population per year, and 0.79–6.5 cases per 100,000 children.⁷ There have been several different genetic polymorphisms associated with TED, however, sample sizes have been small and results variable.⁸ In one large study, it was concluded that TED patients do not have specific genetic predisposition and the disease is more by environmental influences and epigenetic changes.⁹ TED has numerous risk factors, with the most common being female sex, middle age, and most importantly smoking, as this is a modifiable risk factor.⁹ Smoking plays a critical role as it not only increases the development in TED by seven-eight fold, but it also reduces the effectiveness of treatment.⁸ Of note, the risk of TED is more closely associated with smoking after thyroid disease develops, which provides a critical opportunity for intervention in patients with newly diagnosed thyroid disease. Another known risk factor for TED development and progression is treatment with radioactive iodine, as it can result in difficulty maintaining euthymia.¹⁰ Finally, statin use has demonstrated a reduced risk for TED development. However, it is uncertain whether there is a direct effect or it is secondary to cholesterol reduction.^10,11

Clinical Findings and Grading Systems

Signs and Symptoms

The most common sign of TED is upper eyelid retraction, unilateral or bilateral, that occurs in over 90% of patients^12,13 (Figure 1). The resultant wide-eyed appearance allows for chronic eye exposure, especially during sleep. Foreign body sensation, dryness, and tearing occur initially. Over time, severe keratopathy may develop which increases risk of corneal scarring, ulceration, perforation, and endophthalmitis.¹⁴

Figures 1A and B.

A 45-year-old male with active TED demonstrating severe proptosis, upper and lower eyelid retraction and conjunctival injection and edema.

Exophthalmos, or proptosis, is the second most common sign with 60% affected, due to EOM and/or fat expansion, and may also increase the risk of exposure.^12,13 Lagophthalmos, or incomplete eye closure, is seen in half of TED patients.¹³ Elevation of the temporal portion of the upper eyelid contour, known as a temporal flare, is often noted.

EOM dysfunction is seen in 40% of patients, and often results in diplopia if ocular misalignment ensues.¹³ The inferior and medial rectus muscles are most commonly affected, inducing hypotropia (downward deviation) and esotropia (inward deviation) respectively and limiting eye movements if the muscles fibrose. Dull, pressure-like eye pain is experienced by 30% of patients.^12,13 Eyelid edema and erythema, conjunctival injection, and chemosis (conjunctival edema) are less common. Dyschromatopsia (color vision loss) or visual acuity loss secondary to compressive optic neuropathy is seen in about 6% of cases, and implies severe disease.¹³

Curiously, TED may be unilateral or highly asymmetric. It has a vast spectrum of findings and disease severity. Obviously, sight-threatening disease is the greatest concern, consisting of corneal scarring and optic neuropathy, and requires proper identification and urgent treatment.

Differential Diagnosis

Minor symptoms such as tearing and conjunctival injection may appear similar to allergic conjunctivitis, though itchiness and a papillary reaction of the palpebral conjunctiva would be expected in the latter.

Myasthenia gravis may cause variable diplopia and ptosis. Diplopia in TED is not usually variable, and ptosis is not typically associated with TED. Chronic progressive external ophthalmoplegia (CPEO) presents with severe ocular motility deficits and ptosis. It is generally symmetric, painless, and slowly progressive over several years which distinguishes it from TED. Orbital tumors may induce unilateral proptosis and EOM dysfunction, but are unlikely to cause eyelid retraction. Carotidcavernous sinus fistulas may result in marked chemosis, exophthalmos, and conjunctival hyperemia, however, the dilated corkscrew-like vessels seen in the case of a fistula would not be noted in TED.

Other inflammatory disorders including orbital myositis, idiopathic orbital inflammation, IgG4 disease, and granulomatosis with polyangiitis may all present with orbital or eye pain similarly to TED, but they are not associated with eyelid retraction. Orbital myositis is the second most common cause of EOM disease after TED and presents with painful diplopia due to inflammation of one or more muscles, usually unilaterally, with the inferior rectus rarely involved. IgG4-related orbital disease most commonly causes dacryoadenitis, enlarged orbital nerves or thickening of the lateral rectus. Granulomatosis with polyangiitis presents with pulmonary and renal pathologies as well as episcleritis or scleritis, which are not generally seen in TED.

CAS Scoring and VISA Classification

The Clinical Activity Score (CAS) system assesses TED activity using history and external exam findings and is commonly used in research studies. Patients are scored at their initial visit, receiving one point for each of the following symptoms: spontaneous orbital pain, gaze-evoked orbital pain, eyelid swelling, eyelid erythema, conjunctival injection, chemosis, and caruncle or plica semilunaris inflammation.¹⁵ A CAS of three of more at initial encounter is considered active disease. On followup, patients are given an additional point for each of the criteria: ≥2mm increase in proptosis, decrease in motility of either eye by ≥5′, or a decrease in visual acuity ≥1 Snellen line.¹⁵ Scores of four or greater indicate active disease.

The more current VISA (vision, inflammation, strabismus, appearance/exposure) classification assesses severity and activity.¹⁶ Response to therapy is also scored, using a “same, better, worse” categorization. The vision section rules out optic neuropathy by assessing visual acuity, color vision deficits, pupillary responses, and optic nerve appearance. The inflammation section modifies the initial CAS criteria by excluding caruncle/plica semilunaris inflammation (including it under chemosis), and grading chemosis and lid edema on a scale of 0–2. Retrobulbar pain is graded as 0 = no pain, 1 = pain with movement, and 2 = pain at rest. Conjunctival and lid injection are graded as present or absent, and the score of the worst scoring eyelid (range 0–8) is recorded. The strabismus section tracks progression of EOM dysfunction and diplopia. The appearance/exposure section assesses for symptomatic exophthalmos, eyelid retraction, and dryness.

Active vs. Inactive Disease

TED usually develops within 18 months of the development of thyroid disease, but may occur years later. The course of TED follows a predictable curve (Rundle’s Curve) in which active disease lasts for 6–18 months. Disease severity then decreases before plateauing in the inactive or quiescent phase. Although TED is usually self-limiting, the severity at the height of the active phase can be extensive enough to cause bothersome or vision threatening symptoms necessitating surgical intervention. Early intervention in the active phase can limit peak severity, ensuring the inactive plateau phase results in fewer or milder symptoms.

Thyroid Autoantibodies

Graves’ disease results in hyperthyroidism induced by autoantibody stimulation of thyroid stimulating hormone receptor (TSHR). Thyroid-stimulating immunoglobulin (TSI) is the only known TSHR antibody that correlates directly with severity and activity of TED.¹⁷ It may be used as a biomarker in children and adults, however, TED may still occur without autoantibody formation. In a small number of TED patients, elevated TSI is the only initial serologic abnormality with thyroid dysfunction occurring later. Other thyroid autoantibodies that do not correlate with TED characteristics include anti-thyroid peroxidase (anti-TPO) and anti-thyroglobulin (anti-Tg).

Imaging

TED is a clinical diagnosis and does not require imaging for confirmation. However, computed tomography (CT) may assist in the diagnosis of TED by identifying enlargement of EOM bellies with sparing of the tendons (Figure 2). The inferior rectus is most frequently affected, followed in decreasing frequency by the medial, superior, and lateral recti. Least commonly involved are the oblique muscles. CT is useful for orbital decompression surgical planning. MRI will also show EOM enlargement and additionally allows for assessment of orbital fat expansion and may reveal edema suggestive of inflammation.

Figures 2 A and B.

Axial (A) and coronal (B) CT images of a 65-year-old female smoker with compressive optic neuropathy. Note severe enlargement of all rectus muscles impinging on the optic nerves in the retrobulbar orbit.

Treatment

Supportive

The treatment for TED is multifaceted and is based on the degree of clinical activity, progression and morbidity of the patient. Typically, treatment starts with normalization of thyroid function by the endocrinologist and modification of risk factors such as replenishment of vitamin D, if needed, and smoking cessation. Supplemental selenium, 200 micrograms per day for six months has also been shown to improve quality of life and slow the progression of disease in patients with mild TED.¹⁸

Hyperthyroidism is present in 90% of patients and has treatment options of anti-thyroid oral medications, radioactive iodine thyroid ablation and thyroidectomy. Most often in this country, thionamide suppression is the first line therapy to see if remission will occur. The other options are reserved for recurrent or persistent hyperthyroidism and there is evidence that patients with active TED are best treated with thyroidectomy.¹⁹

Ocular specific supportive treatment includes ocular lubricants (drops, gel drops, ointment) and protective eyewear when in the sun, wind and bright light. Sleep masks, eyelid taping and goggle-type devices at night benefit some patients. Head elevation during sleep may help reduce periorbital edema in the morning. The need for psychologic support for this potentially disfiguring disease should also be recognized and local support groups are often helpful.

Corticosteroids

The acute inflammatory phase of the disease is treated medically, if needed, with surgical intervention usually reserved for the post-inflammatory, or “burned out”, chronic phase. Historically, corticosteroids have been the primary treatment for the acute phase. Oral corticosteroids, typically dosed 1 mg/kg of prednisone, can reduce the orbital congestion and soft tissue inflammation, but inadequate response, resurgent disease upon tapering and side effects limit usage today.²⁰ However, the ease and expedience of oral steroids in cases with compressive optic neuropathy and vision loss make it a useful first agent for many practitioners. The superiority of intravenous methylprednisolone over oral prednisone for moderate to severe TED has been shown by several European studies.^21,22

Radiotherapy

Radiotherapy to the orbit is controversial even after many decades of use. The radiation is given in 10 fractions, total dose 2000 cGy, over two weeks, targeting the retrobulbar orbital soft tissues. Its effect is felt to be due to destruction or inhibition of inflammatory lymphocytes, macrophages and orbital fibroblasts and it continues to be used in many areas around the world. It may be used in the early active disease phase, usually in combination with corticosteroids, especially for patients with optic neuropathy, fulminant inflammatory changes or progressive motility restriction.²³ Radiotherapy is contraindicated in diabetics and pregnant women.

Steroid Sparing Agents and Biologics

Steroid sparing antimetabolites have long been used to treat autoimmune diseases. However, use of these drugs in TED has been limited and results have been variable. Several monoclonal antibodies, approved for other indications, have also been investigated for treatment of TED, usually for steroid refractory disease. Since they are off-label treatments, insurance approval and cost issues have limited use.

Rituximab is a monoclonal antibody to CD20 that is expressed on B-lymphocytes. A small case series found benefit for its use in moderate to severe TED, but larger randomized studies have found conflicting results.²⁴

Tocilizumab is a monoclonal antibody directed to the interleukin-6 (IL-6) receptor and it has been effective in reducing inflammatory signs of TED in patients refractory to corticosteroids as measured by a reduction in CAS.²⁵ Like many cytokines, IL-6 is upregulated in TED. This agent has also been administered via a subcutaneous route with favorable clinical results in a case series of nine patients with moderate to severe disease despite a variety of prior treatments.²⁶

Teprotumumab targets the IGF-1 receptor and is the only FDA approved (January 2020) biologic for treatment of TED. Basic research implicated this receptor on the CD-34+ orbital fibrocyte in the pathogenesis of TED. Randomized placebo-controlled studies, sponsored by industry, have shown statistically significant efficacy for proptosis (−3.0 mm vs. −0.3 mm, phase 2 study; −3.32 mm vs. −0.53 mm, phase 3 study), diplopia and CAS (−4.0 vs. −2.5, phase 2 study; −3.7 vs. −2.0, phase 3 study) reduction in steroid naïve patients compared to placebo.^27,28 Entry criteria required patients to be in the acute inflammatory disease stage (CAS greater or equal to four). This intravenous treatment, given in eight doses three weeks apart, is now in widespread use. Our early experience has been with 30 patients: 17 finished, eight in progress, four denied by insurance or deferred after approval, and one who stopped treatment after two infusions due to gastrointestinal symptoms and extreme fatigue. Those who have completed their treatment course, many with history of prior alternative therapies, had overall very favorable results for proptosis and CAS reduction mirroring the aforementioned studies (Figure 3). Its introduction has decreased our need for surgical intervention, especially orbital decompression.

Figures 3 A and B.

Pre (A) and post (B) teprotumumab images for a 67-year-old female. Her CAS reduced from 4 to 0 and there was a 3 mm reduction in her axial proptosis of the right eye.

This medication is expensive and the common adverse events reported with it include muscle spasms (25%), nausea (17%), alopecia (13%), diarrhea (13%), fatigue (10%), hearing impairment (10%), and hyperglycemia (8%). It is contraindicated for those with inflammatory bowel disease and who are pregnant. The long-term efficacy of this biologic remains to be seen and alternate dosing regimen studies have not been performed.²⁹ Its benefit for chronic TED (CAS 0–1), along with retreatment for non-responders and those with a subsequent disease flare-up has been recently reported.^30,31,32

Surgical Management of TED

Surgical management of TED is typically reserved for quiescent disease, often termed the chronic fibrotic phase. The three main pathophysiologic changes requiring surgery in TED are: eyelid retraction, strabismus and proptosis. When proceeding to surgical repair, orbital decompression is traditionally performed first, if needed, followed by strabismus surgery and lastly eyelid surgery. The rationale for this staged approach is improved predictability in the final result.^33,34 The anatomical basis for this doctrine is that orbital decompression surgery can, in and of itself, induce or worsen strabismus, and strabismus surgery can change the position of the eyelids, especially with recession of the inferior rectus. More recent studies have suggested that orbital decompression can be successfully performed at the same time as lower eyelid retraction repair, reducing the number of operations required for rehabilitation, and there are no current studies that have demonstrated inferior results to combined approaches.³⁵ The ultimate decision for combined or staged surgery varies by institution as well as surgeon preferences and experience.

Eyelid Retraction Repair

Eyelid retraction is defined as an increase in the margin to reflex distance 1 or 2 (MRD1, MRD2). These measurements are obtained by shining a penlight at the eye and measuring the distance from the corneal light reflex to the upper and lower eyelid margins, respectively. Eyelid retraction can be addressed surgically in the upper eyelid via either a transcutaneous or a transconjunctival approach. In the transconjunctival approach, the eyelid is everted over a retractor and an incision is made at the superior aspect of the tarsal plate. A cautery device is then used to carefully incise and recess Müller’s muscle, and when deemed necessary, a graded recession of the levator aponeurosis can be performed simultaneously. The transconjunctival recession of Müller’s muscle is an effective procedure with less than 10% failure rate.³⁶

Upper eyelid retraction repair can also be performed through a transcutaneous approach. The levator aponeurosis is accessed through an upper eyelid crease incision and dissection is performed to the tarsal plate. It is then carefully dissected off the tarsal plate and recessed. Spacer grafts, made of porcine dermis, cadaveric dermis, banked sclera, or harvested hard palate or cartilage, can be utilized. When a spacer graft is used, it is typically placed between the superior edge of the tarsal plate and the recessed edge of the levator aponeurosis.

Lower eyelid retraction can be addressed surgically through a transconjunctival approach with recession of the lower eyelid retractors; this can be performed with or without placement of a spacer graft and techniques are largely surgeon dependent. In a large retrospective study of 400 patients, hard palate grafts, free tarsal grafts and scleral grafts were all found to be effective in reducing eyelid retraction, lagophthalmos and dryness.³⁷

Strabismus Surgery

Inflammatory changes with subsequent fibrosis of EOMs will typically lead to the muscles staying in a restricted and inelastic state. This will lead to an eye(s) that is deviated downward (hypotropia), inward (esotropia) or both from involvement of the inferior and medial rectus respectively. The goal of strabismus surgery is to increase the field of binocular single vision, with particular attention paid to alignment in primary gaze. Recessions of the fibrotic muscles are typically the first-choice procedure. Cyclodeviations and combined vertical and horizontal deviations may require special surgical considerations.³⁸

Orbital Decompression

Any of the four bony walls of the orbit can be decompressed, however, most commonly it is the medial wall, floor and lateral walls that are approached in orbital decompression surgery (Figure 4). The goal of this surgery is to increase the volume of the orbit, thus allowing the orbital tissues that have expanded due to ongoing inflammatory changes to fall back into the expanded orbit. Each wall of the orbit when decompressed will typically improve axial proptosis by about 2 mm. Many surgeons will also remove intraconal orbital fat as part of the procedure which can often result in up to 2 mm of reduction in proptosis. The decision to perform a fat-only, a single-wall, or a balanced two or three-wall decompression is typically based on the amount proptosis reduction needed. One of the more common approaches is a balanced medial and lateral wall surgery (Figure 5). The medial wall of the orbit can be accessed through a transcaruncular approach or via an endoscopic approach either in conjunction with an otolaryngologist or by the oculoplastic surgeon. The lateral wall is typically decompressed through a small incision in the lateral canthal area. Patients with compressive optic neuropathy due to crowding in the orbital apex from enlarged EOMs and expanded orbital fat may also need decompression surgery. In these cases, particular attention is given to the posterior orbit, utilizing the same 1,2 or 3 wall approach, to achieve an improvement in visual acuity and field.

Figure 4.

Schematic of the orbital bones commonly removed in orbital decompression surgery. This is a right orbit with medial wall outlined in blue, orbital floor in orange and lateral wall in yellow.

Reprinted with permission from the American Academy of Ophthalmology 2020–21 BCSC Basic and Clinical Science Book.

Figures 5 A and B.

(A) A 50-year-old female with inactive TED with proptosis and upper and lower eyelid retraction. (B) After bilateral orbital bony balanced decompression of the medial and lateral orbital walls.

Orbital decompressions are not without potential risk, the most concerning are loss of vision from optic nerve injury, worsening or new onset diplopia, cerebrospinal fluid leak and infra-orbital hypesthesia. While orbital decompression surgery is a safe and reliable surgery in the hands of an experienced orbital surgeon, several new technologies are being implemented to improve safety such as the use of image-guided orbital navigation and piezoelectric devices that allow for emulsification of bone while minimizing soft tissue injury.^39,40

Conclusion

Thyroid eye disease is the most common inflammatory orbital disorder, is associated with autoimmune thyroid dysfunction and may have protean manifestations. It is a progressive disorder with symptoms and signs that may cause significant facial disfigurement, visual disability and rarely blindness from optic neuropathy or corneal scarring. Although we have a better understanding of its immunologic basis, and now have a biologic medication specifically approved to treat it and alter progression, the clinical course and therapeutic options for each patient must be individualized with input from the multidisciplinary team. The need for surgical treatment for TED is diminishing, especially orbital decompression. We no longer need to wait for “burned-out” fibrotic disease before considering rehabilitation.