Graves Ophthalmopathy

Graves ophthalmopathy is an autoimmune inflammatory condition affecting the orbital tissues. It occurs with Graves disease and, less commonly, with other forms of autoimmune thyroid disease. Rarely it occurs without any current biochemical thyroid dysfunction, termed euthyroid Graves ophthalmopathy.

It reflects the same autoimmune process directed against shared antigens expressed in both thyroid and orbital tissue. It produces a spectrum from mild, self limiting ocular irritation through to severe, sight threatening disease with compressive optic neuropathy.

Accurate assessment of disease activity and severity is essential. Active, progressive inflammatory disease needs a fundamentally different management approach from stable, burnt out disease with fixed, established changes.

Pathophysiology

• T cell mediated autoimmune inflammation targets shared antigens expressed within orbital fibroblasts. The thyroid stimulating hormone receptor itself is one relevant shared target antigen, together with other proposed shared antigens.
• This produces orbital fibroblast activation, with glycosaminoglycan accumulation, extraocular muscle swelling and increased orbital fat volume. Together these increase orbital tissue volume within the fixed bony orbital confines.
• The increased volume produces the characteristic proptosis (forward displacement of the globe) as tissue expands anteriorly.
• Where extraocular muscle involvement is significant, it also produces restrictive strabismus and diplopia.
• In the most severe cases, the swollen extraocular muscles compress the optic nerve at the orbital apex, causing compressive optic neuropathy. This is the most serious, sight threatening manifestation and requires urgent recognition and treatment.
• The disease characteristically follows an initial active, inflammatory phase, during which specific immunosuppressive treatment is most effective.
• A subsequent, generally longer, inactive or "burnt out" phase follows, in which the inflammation has resolved but fixed, established structural changes (fibrosis, established proptosis, fixed strabismus) persist.
• The distinction between active and inactive phases has critical implications for treatment selection.

• Ocular irritation, grittiness, excessive tearing and photophobia, together with periorbital and conjunctival oedema and erythema, characterise the milder, more common end of the disease spectrum. They reflect the underlying orbital inflammatory process.
• More significant manifestations include proptosis (forward displacement of the globe, assessed and monitored using a Hertel exophthalmometer), lid retraction and lid lag, and restrictive extraocular muscle involvement producing diplopia.
• Lid retraction and lid lag can also occur from sympathetic overactivity independent of orbital inflammatory disease, as noted under hyperthyroidism generally, and need careful clinical distinction.
• Diplopia is classically worse on upgaze, reflecting the particularly common involvement of the inferior rectus muscle.
• Compressive optic neuropathy is the most severe, sight threatening manifestation. It presents with progressive visual impairment, reduced colour vision (often an early, sensitive indicator), a relative afferent pupillary defect and, on formal assessment, visual field defect.
• It reflects direct compression of the optic nerve at the orbital apex by the swollen extraocular muscles. It is an ophthalmological emergency, given the risk of permanent visual loss if inadequately or belatedly addressed.
• Corneal exposure and associated keratopathy reflect inadequate lid closure in the context of significant proptosis and lid retraction. This is a further recognised complication needing specific management, given the risk of corneal ulceration and scarring.
• Formal, structured clinical activity scoring (assessing pain, redness, swelling and their recent change) supports objective distinction between active, inflammatory disease and inactive, stable disease, and directly guides treatment.

• Clinical assessment is the essential foundation of assessment and ongoing monitoring. It includes formal exophthalmometry, extraocular muscle movement and diplopia assessment, visual acuity, colour vision and pupillary examination, and structured clinical activity scoring.
• Pupillary examination specifically screens for a relative afferent pupillary defect suggesting compressive optic neuropathy.
• Orbital imaging (computed tomography or, particularly where soft tissue detail is prioritised, magnetic resonance imaging) characterises the pattern and extent of extraocular muscle and orbital fat involvement.
• Imaging is essential where compressive optic neuropathy is suspected, to confirm and characterise the degree of orbital apex crowding and direct optic nerve compression.
• Formal visual field testing and assessment of colour vision give objective, quantifiable assessment of optic nerve function. They are essential both for confirming suspected compressive optic neuropathy and for monitoring response to treatment in this more severe presentation.
• Thyroid function testing and thyroid stimulating hormone receptor antibody testing support confirmation of the underlying Graves disease association. Ophthalmopathy can occasionally precede, follow, or occur independent of the temporal course of the thyroid dysfunction itself.

• Mild disease is managed with supportive measures: lubricating eye drops and, where relevant to nocturnal corneal exposure, ointment, together with sunglasses for photophobia and advice on head elevation during sleep to help minimise periorbital oedema.
• Manage the underlying thyroid dysfunction and, critically, strongly encourage smoking cessation, given its substantial, well established adverse effect on both disease severity and treatment response.
• Achieving and maintaining stable, well controlled thyroid function (avoiding both hyperthyroidism and hypothyroidism) is important across all severity levels of ophthalmopathy, since thyroid dysfunction itself can adversely affect the course of the orbital disease.
• Select the hyperthyroidism treatment carefully (as detailed under Graves disease), given the recognised risk of radioactive iodine treatment exacerbating ophthalmopathy.
• Moderate to severe, active (inflammatory phase) disease is treated with intravenous methylprednisolone, typically given as a weekly pulsed regimen over approximately twelve weeks. The total cumulative dose is limited given the cumulative hepatotoxicity risk with higher doses.
• This is the established first line treatment for active disease not requiring emergency intervention, given demonstrated efficacy for reducing inflammatory activity and proptosis in this disease phase.
• Teprotumumab, an insulin like growth factor 1 receptor inhibitor monoclonal antibody, is an important, more recently established, targeted option for active, moderate to severe disease. It has demonstrated efficacy for reducing proptosis and improving diplopia and is given as an intravenous infusion series. Consider its adverse effects, including hyperglycaemia and hearing disturbance.
• Compressive optic neuropathy is an ophthalmological emergency requiring urgent, high dose intravenous corticosteroid treatment (typically methylprednisolone 500 mg to 1 g intravenously daily for three consecutive days).
• Consider urgent surgical orbital decompression where the response to corticosteroid treatment is inadequate or insufficiently rapid, given the risk of permanent visual loss with any significant delay in relieving direct optic nerve compression at the orbital apex.
• Orbital radiotherapy is used as an adjunct to corticosteroid treatment in some protocols for active, moderate to severe disease, particularly where extraocular muscle restriction and diplopia are prominent. Its use and relative role compared with the pharmacological options varies according to local practice and patient factors.
• Surgical intervention is generally reserved for the inactive, stable disease phase. It includes orbital decompression (for significant proptosis or, urgently, compressive optic neuropathy), strabismus surgery (for stable, established diplopia once the disease has entered its inactive phase), and eyelid surgery (for persistent lid retraction or malposition).
• Surgery during a still active, inflammatory phase carries a substantially higher risk of suboptimal or unstable results, given the ongoing potential for further inflammatory change and progression.
• Where multiple interventions are required, the generally followed sequence is orbital decompression, then strabismus surgery, then eyelid surgery, to optimise functional and cosmetic outcome.

Close, coordinated multidisciplinary management involving endocrinology and ophthalmology, with regular structured monitoring of both thyroid function and ophthalmopathy activity and severity, underpins full management of this condition throughout its typically prolonged, though generally stabilising, disease.