What is the pathogenesis and treatment of exophthalmos in Graves' disease?

From the Guidelines

Exophthalmos in Graves' disease is primarily caused by autoimmune inflammation of orbital tissues, and treatment should focus on controlling thyroid function and managing orbital symptoms to prevent vision loss and improve quality of life. The pathogenesis of exophthalmos in Graves' disease involves TSH receptor antibodies targeting orbital fibroblasts, leading to inflammation, glycosaminoglycan production, and fat expansion, which pushes the eye forward 1.

Key Considerations

• Controlling thyroid function is crucial, using antithyroid medications (methimazole 5-30 mg daily or propylthiouracil 100-300 mg daily), radioactive iodine, or thyroidectomy 1.
• For mild exophthalmos, conservative measures include artificial tears, sleeping with head elevated, and smoking cessation 1.
• Moderate to severe cases require medical intervention with selenium supplementation (200 mcg daily) or corticosteroids (oral prednisone 40-60 mg daily, tapered over 2-3 months, or IV methylprednisolone 500 mg weekly for 6 weeks, then 250 mg weekly for 6 weeks) 1.
• Rituximab (1000 mg IV, two doses two weeks apart) or teprotumumab (10 mg/kg first infusion, then 20 mg/kg every 3 weeks for 7 additional infusions) may be used for severe cases 1.
• Orbital decompression surgery is indicated for optic nerve compression, severe proptosis, or when medical therapy fails 1.

Diagnostic Approach

• Imaging modalities such as MRI or CT scans may be used to assess orbital asymmetry and proptosis, particularly if a mass lesion is suspected or if there is concern for intracranial extension 1.
• MRI is preferred for soft tissue characterization, while CT provides useful information about orbital, muscle, and fat volumes and osseous anatomy, particularly when orbital decompression is a surgical consideration 1.

Management and Treatment

• Prompt treatment is essential to prevent vision loss and improve quality of life, and may involve a combination of medical and surgical interventions 1.
• Patients should be counseled on the diagnosis and treatment options, and carefully monitored for vision loss secondary to compressive optic neuropathy or severe exposure keratopathy 1.
• Referral to an orbital specialist is recommended for patients with vision-threatening disease, moderate to severe exophthalmos, and/or significant orbital pain related to thyroid eye disease 1.

From the Research

Pathogenesis of Exophthalmos in Graves' Disease

• The pathogenesis of exophthalmos in Graves' disease is characterized by an autoimmune process that affects the orbital tissues, leading to glycosaminoglycan deposition, active inflammatory process, fibrosis of the extra-ocular muscles, and fat accumulation within the orbit 2.
• The candidate orbital autoantigens and the cells involved in the development and progression of Graves' ophthalmopathy include T cells, orbital fibroblasts, and B cells through the production of autoantibodies 2.
• The initiation and propagation of the autoimmune process against such antigens involves a complex action of lymphocytes and auto-antibodies, leading to the clinical manifestations of proptosis, chemosis, periorbital edema, and altered ocular motility 2.

Treatment of Exophthalmos in Graves' Disease

• Most patients with Graves' ophthalmopathy can be treated conservatively, but a few require anti-inflammatory or surgical therapy to relieve symptoms and preserve vision 3.
• Methotrexate therapy may be a useful therapeutic approach in the treatment of isolated Graves ophthalmopathy, particularly in patients who do not respond to oral and intravenous steroids 4.
• Orbital decompression surgery can provide rapid relief of inflammatory changes and improve symptoms in patients with Graves' ophthalmopathy 5.
• Future specific therapies under investigation are aimed against the autoantibodies, the orbital fibroblasts, or the peroxisome proliferator-activated receptor gamma (PPARgamma), which regulates fatty acid storage and glucose metabolism 2.

Clinical Manifestations of Exophthalmos in Graves' Disease

• The clinical manifestations of exophthalmos in Graves' disease include proptosis, chemosis, periorbital edema, and altered ocular motility, as well as conjunctival and eyelid edema and congestion, restricted ocular movement with resultant diplopia, and optic nerve compression leading to compressive optic neuropathy 6.
• The correlation of TSH-Abs levels with Graves' ophthalmopathy activity is used clinically as a marker of disease activity, to aid prediction of the disease course, and to support diagnosis in patients with no clinically significant thyroid disease 2.