BASICS

DESCRIPTION

Thyroid eye disease (TED) is a chronic orbital inflammatory disease, commonly associated with hyperthyroidism (90%) but occasionally with hypo- or euthyroid status.

EPIDEMIOLOGY

Incidence

Female: Male ratio of 5:1 (16 women: 3 men per 100,000 population)

Prevalence

Occurs in 25–50% of patients with Graves’ disease (hyperthyroidism)

RISK FACTORS

• Graves’ disease

• Hashimoto’s thyroiditis

• Smoking

Genetics

Genetic loci implicated include (HLA, 6p21-3), cytotoxic T-Lymphocyte antigen-4 (CTLA-4, 2q33), tumor necrosis factor (TNF), interferon-gamma, intracellular adhesion molecule (ICAM-10), and thyroid stimulating hormone receptor (TSH-R).

GENERAL PREVENTION

Avoid smoking (odds ratio for smokers vs. nonsmokers is 7.7)

PATHOPHYSIOLOGY

• Autoimmunity

– Autoantibodies acting specifically on fibroblasts surface TSH-R and insulin-like growth factor-1 receptor (IGF-1R) (1)

– Activated fibroblasts secrete chemokines and cytokines promoting lymphocyte migration and B-cell maturation.

– Prostaglandin-E2 (PGE2), PGD-2, Interleukin-6 (IL-6), and IL-8 may stimulate orbital fibroblasts to produce glycosaminoglycans (GAG) and adipose tissue, increasing orbital mass.

• Smoking

– Cigarette smoking has been found to be a risk factor for the development and severity of TED (2).

ETIOLOGY

Autoimmune (see pathophysiology)

COMMONLY ASSOCIATED CONDITIONS

• Hyperthyroidism (Graves’ disease) in 90% of cases.

• Autoimmune conditions (diabetes, myasthenia gravis)

DIAGNOSIS

HISTORY

• Known thyroid disease with signs and symptoms (palpitations, weight loss, tremor, proximal muscle weakness)

• Proptosis

• Eyelid retraction

• Diplopia

• Ocular pain

• Red eye, foreign body sensation

• Vision loss

• Smoking

• Symptoms of associated myasthenia (double vision, ptosis, muscle weakness)

PHYSICAL EXAM

• Conjunctival redness over the insertion of the extraocular muscle insertion, exposure keratopathy superior limbic conjunctivitis, and dry eye.

• Chemosis

• Lid edema

• Exophthalmos

• Strabismus/ophthalmoplegia

• Optic neuropathy

• High intraocular pressure

DIAGNOSTIC TESTS & INTERPRETATION

Lab

Initial lab tests

• TSH, FT3, FT4, and thyroid stimulating immunoglobulin (TSI).

• Acetylcholine receptor antibody testing if ocular myasthenia is suspected

Follow-up & special considerations

Endocrinologic assessment for monitoring and correction of the thyroid status

Imaging

• CT scan of the orbit

– Can be ordered (axial and coronal views) as a baseline or in atypical cases and can show enlarged extraocular muscle, orbital fat expansion, straightening of the optic nerve, and muscle crowding at the orbital apex

– CT scan should be ordered in all cases of suspected thyroid compressive optic neuropathy to study the apical region of the orbit especially before orbital decompression.

Diagnostic Procedures/Other

• Complete ophthalmologic evaluation

– Slit-lamp examination with fluorescein staining: Rule out exposure keratopathy

– Goldman applanation tonometry in primary position and upgaze positions.

– Pupillary evaluation: To detect RAPD in compressive optic neuropathy

– Hertel exophthalmometry: To measure proptosis

– Orthoptic evaluation: For diplopia due to strabismus

– Dilated fundus examination: To assess the optic nerve

• Visual field assessment is important in case of compressive optic neuropathy.

Pathological Findings

The extraocular muscles reveal lymphocyte and plasma cell infiltration along with edema within the endomysium of the extraocular muscles.

DIFFERENTIAL DIAGNOSIS

• Orbital inflammatory diseases

– Idiopathic orbital inflammatory disease (orbital pseudotumor)

– Sarcoidosis

– Wegener’s granulomatosis

– Orbital infiltration (lymphoma, metastatic disease)

• Ophthalmoplegia

– Ocular myasthenia gravis

TREATMENT

MEDICATION

First Line

• Local symptomatic management (Mild disease)

– Smoking cessation

– Artificial tears, cold compressors

– Patching or prisms for diplopia

Second Line

• Moderate–severe disease (severe congestive orbitopathy/exposure keratopathy/optic neuropathy)

– Steroids: Oral dose of 60–100 mg can be administered over 2–3 months as a temporizing measure. Intravenous steroids on various pulse regimens for a cumulative dose of 8 g can also be given and appear to be more effective and better tolerated than oral steroids (3).

– Orbital radiotherapy: This can be given along with steroids for a cumulative dose 20 Gy, but the data on its efficacy is conflicting. It is not effective in treating proptosis but should be considered in patients with active disease with optic neuropathy refractory to maximal medical therapy and/or surgical decompression (4).

– Orbital decompression: Removal of parts of the orbital bony walls (medial, inferior, and lateral) and fat for compressive optic neuropathy or severe proptosis and corneal exposure

– Immunomodulatory drugs: Rituximab, rapamycin, and etanercept have been recently found beneficial in TED (5).

ADDITIONAL TREATMENT

General Measures

Uncontrolled thyroid function is associated with more severe TED.

Issues for Referral

• The complex nature of Graves’ disease requires multidisciplinary team approach of endocrinologist/orbital surgeon/radiation oncologist.

• Corneal exposure and compressive optic neuropathy are sight-threatening signs and should be managed expeditiously by referral to an orbital/neuroophthalmology specialist.

Additional Therapies

Botulinum toxin can be give in the upper lids to relieve lid retraction or into the extraocular muscles as a temporizing measure for diplopia.

SURGERY/OTHER PROCEDURES

• Orbital decompression: A combination of medial/inferior/lateral bony walls can be decompressed in proptosis, exposure keratopathy, and optic neuropathy.

• Strabismus surgery is usually done following orbital decompression for diplopia.

• Lid surgery for lid retraction and dermatochalasis can be done with or following strabismus surgery.

ONGOING CARE

FOLLOW-UP RECOMMENDATIONS

• Patient with mild disease and no exposure keratopathy or optic neuropathy can be followed q 3–6 months.

• Patients with advanced exposure keratopathy and/or compressive optic neuropathy require immediate attention (steroids/radiation/orbital decompression).

• Patients receiving radioactive iodine ablation therapy for hyperthyroidism should be treated prophylactically with steroids to avoid activation of TED after treatment.

• Patients finishing radioactive ablation therapy should be treated quickly with thyroid hormone replacement as the sudden change to hypothyroidism can trigger TED activation.

Patient Monitoring

• Regular periodic ophthalmic evaluation including pupillary assessment, color vision, visual fields

• Patients with intermittent diplopia should be assessed for possible associated myasthenia gravis.

• IV steroids pulse regimen for active disease have been associated with hepatic toxicity especially in cumulative doses above 8 g. Liver function testing is recommended during IV steroid pulse therapy.

• Oral bisphosphonate should be given to patients requiring steroid treatment to prevent osteoporosis.

PATIENT EDUCATION

• Patients are told to watch for color desaturation or decreased vision (signs of optic neuropathy)

• Emphasize the importance of smoking cessation

• Graves’ disease foundation (www.ngdf.org)

PROGNOSIS

• Rundle’s curve

– Active (inflammatory) phase (6 months to 5 years)

– Inactive (Fibrotic) phase: Stable clinical signs for at least 6 months suggest that patient has entered the inactive phase.

COMPLICATIONS

• Corneal exposure/ corneal ulceration

• Compressive optic neuropathy

• Diplopia

• Glaucoma

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