Thyroid Eye Disease

Introduction

Thyroid eye disease (TED) is an orbital inflammatory disorder that is associated with thyroid autoimmune diseases and causes expansion and scarring of orbital fat and striated muscle.

Although it is self-limited, TED may significantly disrupt cosmesis, vision, and quality of life (QOL).

Epidemiology, Risk Factors, and Associated Conditions

TED is the most common orbital disease globally, with a prevalence rate estimated between 0.5% and 2%, and with females outnumbering males by 4:1. It usually occurs between the second and sixth decade of life and involves all races.

Risk factors for developing TED include a positive family history, smoking, life stressors, and poorly controlled hypothyroidism after radioactive iodine. Predictors for more serious involvement by TED include male sex, increasing age, smoking, and a rapid onset of orbitopathy.

Cigarette smoking is strongly correlated with both the development of TED and with its severity.

Patients with TED have an increased probability of developing associated immune diseases, including superior limbic keratitis, myasthenia gravis, diabetes mellitus, alopecia, and vitiligo.

Pathogenesis

TED often occurs in conjunction with autoimmune thyroid diseases, such as Graves' disease (90%) or Hashimoto thyroiditis (3%); 90% of orbitopathy patients have current or previous abnormal systemic thyroid hormone levels, whereas others may develop abnormal levels in the future.

In Graves’ disease, an aberrant population of lymphocytes produce thyrotropin-receptor antibodies, also known as thyroid-stimulating hormone receptor (TSH-R) antibodies. Differing subtypes may cause more, less, or unchanged levels of serum thyroxine.

Similar receptor sites on skin and orbital fat and muscle fibrocytes also may be targeted by these autoantibodies in Graves' disease, resulting in orbitopathy in 50% and dermopathy (pretibial myxedema or acropachy) in 5%–10%.

The target cell in TED is the CD34 ⁺ pluripotential orbital fibrocyte, present in orbital fat, striated muscle, and lacrimal gland. These cells have increased thyrotropin receptors (TSH-Rs) and insulin-like growth factor receptors in close apposition on their surface. Binding of circulating thyrotropin-receptor antibodies to these fibrocyte receptors may cause cross-talk, which induces adipogenesis and hyaluronic acid production, resulting in expansion and remodeling of orbital tissues. The process is enhanced by activation of T helper cells with the release of cytokines (including interleukin-16) that potentiates the inflammatory cascade ( Fig. 12.13.1 ).

Clinical Presentation: Disease Severity and Activity

TED presents with a spectrum of clinical features determined by which orbital tissues are involved. The pattern and extent of involvement are graded as “disease severity.”

Approximately two-thirds of patients with TED develop primarily fat expansion, often in association with focal levator muscle inflammation, resulting in eyelid retraction, proptosis, and ocular exposure. This pattern typically evolves indolently in a younger, predominantly female population ( Fig. 12.13.2 ).

The remaining third have significant enlargement of one or more extraocular muscles and present with more severe features, including congestion and edema of the conjunctiva and eyelids, restricted ocular ductions with diplopia, and dysthyroid optic neuropathy (DON) resulting from apical compression of the optic nerve by the swollen muscles. Muscle-centric disease usually develops more rapidly in an older population with a more balanced sex distribution and is more likely to be associated with smoking and a positive family history of TED ( Fig. 12.13.3 ).

TED has a biphasic course, with a progressive (“active”) phase lasting 6–18 months, followed by a stable (“inactive”) phase. These disease phases are graded as “clinical activity.” “Rundle's curve” is a graph of orbital disease severity against time ( Fig. 12.13.4 ), with a steeper slope in the progressive phase reflecting more aggressive disease. Immunomodulators and radiotherapy (RT) administered during the early active phase may limit the destructive consequences of the immune cascade. Surgery is usually performed in the postinflammatory phase for orbital cosmesis, comfort, and function but may be needed during the progressive phase to prevent vision loss from DON or corneal breakdown.

Recurrence of TED occurs in less than 10% of cases.

Diagnosis

Diagnosis of TED is based on three aspects of the disease:

• 1.

  Clinical features: Characteristic findings such as lid retraction combined with proptosis and limited motility are highly suggestive of TED, particularly when bilateral.

• 2.

  Thyroid function and antibody tests: Abnormal thyroid function tests (thyroxine and TSH levels) or a history of thyroid dysfunction help confirm the diagnosis, although 10% of TED patients may be euthyroid at onset. The presence of TSH-R antibodies has high sensitivity for active Graves’ disease.

• 3.

  Orbital imaging: CT or magnetic resonance imaging (MRI) may help confirm the diagnosis, particularly for atypical or uncertain clinical situations. CT scan documents fat or muscle enlargement and apical crowding, and allows assessment of bony walls and sinuses for possible surgical decompression. Contrast CT scans may show enhancement of the extraocular muscle sheaths or stranding of surrounding orbital fat in the active inflammatory phase or lucent spaces in the extraocular muscles in the inactive phase. MRI identifies edema within the extraocular muscles on T2 or STIR (Short Tau Inversion Recovery) sequence in active disease.

Evaluation of Disease Severity and Activity

Early diagnosis permits an accurate evaluation of TED, including assessment of disease severity and activity and identification of those individuals at high risk of developing more serious complications.

VISA Classification

This recording form grades both disease severity and activity using subjective and objective inputs ( Fig. 12.13.5 ). It organizes the clinical features of TED into four severity parameters: V (vision, DON); I (inflammation, congestion); S (strabismus, motility restriction); and A (appearance, exposure). A summary grade for each severity parameter is recorded at the end of the form so that directed therapy is chosen depending on the parameters most involved.

Activity is based not on the inflammatory score but by subjective or objective evidence of progression for any of the four severity parameters since the previous visit.

The layout follows the usual sequence of the eye examination and facilitates comparison of measurements between visits, as well as data collation for research.

On the first visit, the date and rate of onset and historic progress of both the systemic and orbital symptoms are recorded, defining characteristics of the disease course. Additional questions also determine risk factors for more serious TED outcomes associated with extraocular muscle involvement, including smoking, family history, and diabetes. A first-visit form (two pages) and follow-up form (one page) may be downloaded from the International Thyroid Eye Disease Society website ( http://thyroideyedisease.org/ ).