Synonyms: Graves' opthalmopathy, Thyroid eye disease.
Graves orbitopathy is defined as a potentially progressive, generally self limiting auto immune process involving the eye associated with hyperthyroidism. It is in fact the most common cause of proptosis and orbital inflammatory disorder in adults.
Graves disease is common in females. Females out number males by the ratio of 4:1. This disease progresses more rapidly in men when compared to women.
Graves disease is common during the 4th to 6th decades.
These factors are known to play a role in the pathogenesis of Graves disease. About 60% of the affected individuals have a positive family history of thyroid disease. Patients with Graves orbitopathy are known to express certain human leukocyte antigens (HLA) more often than control group without the disease (HLA - B8, DR3, and DQA 1 haplotypes). These HLA types have been known to be associated with Graves disease. HLA DR ß1 subtype may offer protection against Graves disease. Immunopathogenesis of Graves disease: Antigen presenting cells (macrophages and dendritic cells) bind antigens and present them to CD4 helper T cells. This activates the T cells. For this activation process to occur the antigen should bind to the major histocompatibility molecules on the antigen presenting cells. HLA molecules influence the selection of antigens that can be presented to T cells. Subsequent activation of these T cells results in a cascade of events leading to autoimmune recongnition of self antigens which may occur in the thyroid and extra thyroid tissues like orbit. Thymus plays an important role in recognizing self from external antigens. This process is known as negative and positive selection. Negative selection at the thymus helps the human body to prevent immune reaction against its own tissues. In other words if an HLA molecule on an antigen presenting cell binds to a self antigen and presents it to a T cell whose receptor recognizes the HLA molecule antigen complex. But this T cell is negatively selected at the level of thymus preventing autoimmune reactions from occurring. If this process of negative selection fails for some reason autoimmune reactions may ensue. Certain HLA types like HLA - B8, DR3 and DQA 1 may fail to present self antigen to the T cells present in the thymus, causing them to be directly released to the periphery bypassing the negative selection mechanism of thymus causing autoimmune reactions.
Environmental factors predisposing to Graves disease:
1. Thyroid surgery
3. Radiation exposure
4. Thyroid inflammation
6. Yersinia infections (controversial) - Molecular mimicry may be involved in this pathogenesis.
Graves hyperthyroidism is an autoimmune disorder that involves binding of stimulatory autoantibodies to the TSH receptors seen in the thyroid follicular cells. Different types of autoantibodies have been described. These antibodies on binding to the TSH receptors of follicular cells frees these cells from the control of the pituitary negative feed back mechanism. Hence these patients have depressed TSH and elevated thyroid hormone levels.
Graves orbitopathy is a multifactorial disease involving mechanical, immunologic and cellular processes. Graves orbitopathy demonstrates excess glycosaminoglycans. Hyaluronan is the predominant glycosaminoglycans involved. It is always associated with expansion of both orbital connective tissues and extraocular muscle fibers. There is evidence for oversynthesis and underdegradation of glycosaminoglycans in these patients. There is also associated adipose tissue expansion which increases the orbital volume.
Clinically the inflammation associated with Graves orbitopathy may be classified into two types: Type I inflammation: In this condition the orbital fat and connective tissue of the orbit alone are involved.
Type II inflammation: These patients have severe extraocular muscle involvement.
Patients with type I inflammation have better prognosis and rarely develop visual loss. Patients with type II inflammation however are more prone for aggressive disorder associated with diplopia, lid retraction and optic neuropathy. Some patients may show evidence of both type I and type II involvement. Clinical evaluation: Clinical signs can be categorized using Werner's classification system for thyroid oculopathy. It can be easily remembered using the pneumonic NOSPECS.
Class 0 (No signs): This represents subclinical disease without apparent signs and symptoms. Early ophthalmopathy may manifest in subtle ways like tearing, photophobia, foreign body sensation, mild conjunctival injection, increased intraocular pressure etc. Superior limbic keratoconjunctivitis has been recognized as a significant risk factor for the development of Graves orbitopathy.
Class I: (Only signs): This group consists of lid retraction and stare only. This is due to elevated sympathomimetic activity or fibrosis of the lid tissues causing lid retraction. Lid lag on downward gaze is commonly seen.
Class II: (Soft tissue swelling): This group is characterized by soft tissue involvement. The signs include deep conjunctival injection, especially over the insertion of rectus muscles. There may be associated edema of caruncular area. Inflammation may cause periorbital oedema and erythema.
Class III: (Proptosis): This includes exophthalmos. Extraocular muscles are inflammed, there is also associated increase in orbital fat volume resulting in axial proptosis. These patients will manifest increased resistance to posterior displacement of globe (retropulsion).
Class IV: (Extraocular muscle):This stage is characterized by extraocular muscle involvement. The muscle involvement starts with accumulation of inflammatory cells and fluid. This is characterized by diplopia which is worse early in the morning. This is due to the fact that fluid tends to accumulate in the orbit when the patient is lying down. Forced duction test is positive.
Class V: (Corneal exposure):This stage involves corneal involvement. These patients have exposure keratitis, eyelid dysfunction, proptosis, tear film abnormalities, Bell phenomenon secondary to muscle restriction.
Class VI: (Sight loss): This stage involves visual loss secondary to optic nerve injury due to progressive proptosis. As the eye becomes prominent, the optic nerve becomes stretched. It is important to assess visual acuity, color vision and pupillary reactions in these patients.
Imaging: CT scan is the best imaging modality for evaluation Graves orbitopathy. CT scans show muscle belly enlargement with sparing of tendinous insertions. It also shows increase in orbital fat volume, lacrimal gland enlargement and compression of optic nerve at the orbital apex.
The goal of treatment is to ensure that these patients reach an euthyroid state at the earliest. Steroids is one of the most important treatment modality in these patients. Therapy is started with prednisolone and often is prescribed in dosage of 60 - 100 mg per day. Steroids reduce inflammatory reactions in the orbit. It also reduces fibrosis of extraocular muscles.
Retrobulbar steroid injections are used to minimize systemic effects of steroids. Radiation therapy: Consists of delivering low dose radiation in multiple fractions to the orbits. 2000 - 2500 cGy. Radiation is useful because it is effective in combating acute inflammation. Radiation is helpful against lymphocytes in particular.
This involves orbital decompression, strabismus repair, and correction of eyelid malpositions. Decompression may be necessary urgently if there is evidence of compressive optic neuropathy with severe proptosis.