Graves’ Disease: Complications
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The closest thing to seeing an ophthalmologist.
A comprehensive detailed piece about thyroid eye disease (TED) symptoms, diagnosis and treatment options.
For those interested in finding out what their TED symptoms mean.
Article covers -
1) Thyroid storm
2) TED (Graves’ orbitopathy(GO))
3) Thyroid dermopathy and Acropachy
4) Clinical abnormalities of the heart
TED specific -
1. Removal of risk factors (refrain from smoking, correction of thyroid dysfunction, oral steroid prophylaxis after radioactive iodine therapy, antioxidant therapy with seleniomethionine) are fundamental to prevent progression of mild GO to more severe forms.
2. In moderate-to-severe and active GO, intravenous glucocorticoids are the first-line treatment, second line treatments include cyclosporine, orbital radiotherapy, rituximab (controversial). Novel biologicals, such as teprotumumab and tocilizumab are under investigation. Rehabilitative surgery (orbital decompression, squint surgery, eyelid surgery) is often required.
3. Clinical manifestations of GO reflect remodeling of the orbital space related to the enhanced orbital volume, due to an increase in retroocular fibroadipose tissue and swelling of extraocular muscles.
4. Because the orbit is a rigid, bony structure anteriorly limited by the orbital septum, the increased orbital volume deriving from cell proliferation, inflammatory infiltration and edema, results into enhanced intraorbital pressure, forward displacement of the globe (proptosis or exophthalmos), extraocular muscle dysfunction causing diplopia and/or strabismus, soft tissue changes with periorbital edema, conjunctival hyperemia and chemosis.
5. If proptosis, which can be considered a form of spontaneous decompression, is severe, subluxation of the eye may occur. Proptosis is responsible for corneal exposure which may be particularly dangerous at night for the incomplete eyelid closure (lagophthalmos), and may result into sight-threatening corneal ulceration.
6. The enlarged muscle volume may cause optic nerve compression (dysthyroid optic neuropathy), especially if the orbital septum is tight and proptosis is minimal. Optic nerve compression is particularly evident at the orbital apex and may be responsible for sight loss.
7. Orbital inflammation and related anatomical changes may cause venous and lymphatic congestion that contribute to periorbital edema and chemosis.
8. With time inflammation subsides and muscle fatty degeneration and fibrosis may contribute to further extraocular muscle restriction and strabismus, which, at this stage, can only be corrected by surgery.
9. Clinical features of GO include soft tissue changes, exophthalmos, extraocular muscle dysfunction, corneal abnormalities, and optic nerve involvement
10. Soft tissue changes include eyelid edema and periorbital swelling, eyelid erythema, conjunctival hyperemia and chemosis, inflammation of the caruncle or plica.
11. Proptosis, i.e., protrusion of the eye (exophthalmos), is usually measured by Hertel exophthalmometer; normal values are usually less than 20 mm, but vary with race, age, gender, degree of myopia,
12. Extraocular muscle dysfunction is responsible for diplopia (double vision), which can be subjectively defined as intermittent (i.e., present only when fatigued or when first waking), inconstant (i.e., present only at extremes of gaze), or constant (i.e., present also in reading positions and primary gaze); objective assessment of extraocular muscle functioning can be done by several methods, including measurement of duction in degrees
13. Palpebral aperture may be increased due to several factors, including upper and/or lower lid retraction, and proptosis. Lid retraction and proptosis are responsible for corneal exposure, which may lead to corneal epithelium damage (punctate keratopathy), corneal ulceration and perforation.
14. The incomplete eye closure at night (lagophthalmos) and the absence of Bell’s phenomenon (no upward eye rotation on attempted eye closure) are risk factors for corneal damage (92, 94). Intraocular pressure is often increased, particularly in upward gaze, but this abnormality rarely progresses to true glaucoma.
15. Dysthyroid optic neuropathy, due to optic nerve compression at the orbit apex by swollen extraocular muscles, or, less frequently, to optic nerve stretching in cases of marked proptosis or eye subluxation, is a sight-threatening expression of GO. It can be diagnosed by fundoscopy showing disc swelling, reduced visual acuity, abnormal color vision test, contrast sensitivity, perimetry, visual-evoked potentials, and pupillary responses (95).
16. NOSPECS classification of eye changes of Graves’ disease
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17. Symptoms of GO (Table 4) include, in addition to changes in ocular appearance related to periorbital swelling and proptosis, excess lacrimation, photophobia, grittiness, pain in or behind the eyes, either spontaneous or with eye movements, diplopia of different severity with or without strabismus, blurred vision, which may clear with blinking (due to excessive lacrimation) or covering one eye (reflecting extraocular muscle impairment), or may persist (probably reflecting optic neuropathy, particularly if associated with gray areas in the field of vision). In addition to reduced visual acuity, optic nerve involvement can be heralded by decreased color perception. Diplopia may be absent if extraocular muscle involvement is symmetrical in both eyes.
Table 4. Symptoms associated with Graves’ orbitopathy
1. Changes in eye appearance, particularly eyelid or periorbital swelling, eye bulging
2. Excessive lacrimation, often more pronounced on waking
3. Incomplete closure of eyes at night (lagophthalmos), as reported by the partner
4. Photophobia, need to protect eyes with dark lenses
5. Increased eye “sensitivity” to irritative factors other than light (e.g., wind, smoke, pollution)
6. Ocular discomfort, described as grittiness, foreign body or sandy sensation, often defined as “allergy”
7. Ocular pain, either related or unrelated to eye movements
8. Neck ache, with abnormal head posture (torcicullum)
9. Diplopia
a. Intermittent: present only when tired or on waking
b. Inconstant: present only at extremes of gaze
c. Constant: present also in primary and reading positions
10. Blurred vision
a. Disappearing with blinking
b. Not disappearing with blinking
11. Reduced color perception
18. Clinical manifestations of GO have a profound negative impact on quality of life and daily activities of affected individuals
19. ... a GO-specific quality of life (GO-QoL) questionnaire was developed and validated in clinical studies (99, 100-102). This questionnaire (dowloadable from EUGOGO website at eugogo.eu) is composed of 16 questions, 8 concerning the consequences of diplopia and deceased visual acuity on visual functioning, and 8 regarding the consequences of changes in physical appearance on social functioning. The Go-QoL is a useful tool for self-assessment of treatment outcomes for GO
20. Definition of GO severity is somehow arbitrary and may reflect different views (11, 23). According to the most recent EUGOGO definition (92), mild GO is characterized by one or more of the following features: minor lid retraction (<2 mm), mild soft tissue involvement, exophthalmos <3 mm above normal for race and gender, transient or no diplopia, and corneal exposure; the above features usually have a minor impact on daily life to justify immmuno-suppression or surgical treatment
21. moderate-to-severe GO have any one or more of the following: lid retraction >2 mm, moderate or severe soft tissue involvement, exophthalmos >3 mm above normal for race and gender, inconstant or constant diplopia; Patients in this category have an impact on daily life as to justify immunosuppression (if GO is active) or surgical intervention (if GO is inactive);
22. sight-threatening GO is due to dysthyroid optic neuropathy (DON) or corneal breakdown, and warrants immediate intervention (Table 5)
23. Assessment of severity is particularly relevant to decide on whether a given patient should be treated by aggressive treatments (either medical or surgical) or simply by local or general supportive measures
24. The other important feature of GO is its activity. Although, as stated above, GO natural history is not completely understood, it is commonly accepted that GO undergoes an initial phase of activity, characterized by progressive exacerbation of ocular manifestations until a plateau phase is reached; GO then tends to remit spontaneously, but remission is invariably partial
25. In the inactive phase (burnt-out GO), only residual ocular manifestations are present (e.g., proptosis, strabismus due to muscle fibrotic changes), but inflammation has subsided and it is unlikely that it may flare up.
26. It is unknown how long this process takes to be completed, but it is widely believed that it takes between 6 months and two years.
27. Recognition of the different phases of the disease is important, because active disease, basically characterized by the presence of inflammation, can respond to immunosuppressive treatments, which are largely ineffective when GO is burnt-out.
28. A useful tool to assess GO activity is represented by the Clinical Activity Score (CAS) ... GO is generally defined active if CAS is >3.
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29. Diagnosis of GO is usually easy on clinical grounds and by careful ophthalmological examination. Although not necessary in most Graves’ patients, CT scan or MRI of the orbit confirm diagnosis by showing enlarged extraocular muscles (without involvement of the tendon) and/or increased orbital fibroadipose tissue
30. Modest extraocular muscle enlargement and increased fibroadipose tissue volume are often found in Graves’ patients without clinical manifestations of ocular involvement.
31. Orbital imaging is very useful to detect signs of optic nerve compression, which support the diagnosis of optic neuropathy.
32. Imaging is required in asymmetrical or, particularly, unilateral forms of GO, to rule out that proptosis, periorbital swelling, inflammation, or diplopia be due to disorders other than GO (12, 106). The latter include primary or metastatic orbital tumors, vascular abnormalities (e.g., carotid-cavernous sinus fistula, carotid aneurysm, cavernous sinus thrombosis, subarachnoid hemorrhage, subdural hematoma), granulomatous disorders, IgG4-related ophthalmic disease
33. Management of GO is based on a multidisciplinary approach which involves endocrinologists, ophthalmologists, orbit surgeons, radiologists and radiotherapists.
34. The therapeutic approach to a GO patient should be based on both severity and activity of the disease, the former being the feature to assess first.
35. Mild GO. Most patients have mild GO, which does not require particularly aggressive treatments and often is self-limiting (92, 110, 111).
36. If GO activity is modest, simple local measures can be suggested to obtain symptomatic relief until GO is burnt-out (Table 7).
37.
1) Photophobia can be mitigated by sunglasses;
2) grittiness due to corneal exposure can be controlled by artificial tears and topical lubricants, particularly indicated in the presence of lagophthalmos;
3) the latter may require taping the eyelids shut at night;
4) eyelid retraction can be controlled (with a variable degree of success) by b-blocking drops (useful for the increased intraocular pressure) or by botulinum toxin injections (112);
5) elevation of the bed may be helpful to reduce periorbital swelling due to congestion; 6) mild diplopia often is controlled by prisms (if they are tolerated).
38. Reassurance is an important issue, and the patient must be informed that his/her eye disease is unlikely to progress to more severe forms, usually stabilizes, and often ameliorates spontaneously.
39.
1) Control of thyroid dysfunction is fundamental, because progression often is associated with hyper- or hypothyroidism
2) refrain from smoking is also essential, because it is associated with a decreased chance of developing proptosis and diplopia (113), and decreases the likelihood to develop severe GO
40. In a subset of patients with mild GO, the impact of GO on the quality of life is so pronounced as to justify the risk of immunosuppression (or surgery) as for moderate-to-severe GO
41. A recent randomized controlled trial performed by EUGOGO in a large cohort of patients with mild GO showed that selenium supplementation for 6 months has beneficial effects on mild GO compared with placebo and can often prevent its progression to more severe forms (114). Thus, selenium, for its anti-inflammatory and immunomodulatory actions, should be considered both as a therapeutic tool for mild GO and a preventive measure.
42. Whether selenium is also useful as an adjuvant therapy in patients with moderate-to-severe GO is presently unsettled.
43. Moderate-to-severe GO. Management of moderate-to-severe GO depends not only on severity, but also on activity of the orbitopathy (Table 8). Medical treatment is likely to be beneficial in patients with active GO, with florid signs and symptoms of inflammation, recent-onset extraocular muscle dysfunction, recent progression of the ocular abnormalities as a whole.
44. On the contrary, in long-standing GO, with chronic proptosis and residual, stable diplopia and/or strabismus, but no no evidence of inflammation, medical treatment has little chances to produce favorable effects, and the surgical, rehabilitative approach is preferable
45. Dysthyroid optic neuropathy, the most severe expression of the orbitopathy, is a clinical, sight-threatening emergency, which requires immediate treatment. If there is no response to medical treatment (high-dose intravenous glucocorticoids), orbital decompression is warranted
46. Glucocorticoids are the mainstay in the medical treatment of GO (12, 92, 116, 117). They have been used for decades because of their anti-inflammatory effects, but also because they exert immunosuppressive actions useful to control the course of the orbitopathy
47. Locally (subconjunctivally or retrobulbarly) given glucocorticoids are less effective than systemically given glucocorticoids ) (11, 92), although favorable responses in terms of improvement of diplopia and reduction in extraocular muscle dysfunction have been reported with in a recent randomized clinical trial of periocular injections of triamcinolone acetate
48. In the last 20 years the intravenous route has become the most commonly used (101) and currently represents the first-line treatment for moderate-to-severe and active GO (92). Intravenous glucocorticoids are more effective, with a rate of favorable responses reported until few years ago of about 80-90% versus 60-65% with oral glucocorticoids (117, 119), and better tolerated than oral glucocorticoids
49. Glucocorticoids are most effective on soft tissue, inflammatory changes, recent-onset extraocular muscle dysfunction, and dysthyroid optic neuropathy, whereas proptosis and long-lasting eye muscle impairment are less responsive
50. Orbital radiotherapy is the other non-surgical mainstay in the management of GO ... Preexisting retinopathy associated with diabetes mellitus or hypertension represents a contraindication to its use
51. Orbital decompression is a milestone in the management of GO. It is aimed at increasing the space available for the increased orbital content by removing part of the bony walls of the orbit and/or the orbital fibroadipose tissue (157). It is indicated in patients who have impending sight loss due to optic neuropathy and do not respond promptly to intravenous glucocorticoids (157). Other important indications for decompressive surgery are represented by corneal damage due to eyeball exposure in patients with marked proptosis, or by recurrent subluxation of the globe, which may stretch the optic nerve and cause sight loss
52. Rehabilitative surgery includes surgery for strabismus or eyelid retraction.
53. Extraocular muscle surgery is aimed at correcting residual diplopia after medical and/or surgical treatment of GO. Timing of surgery is crucial, because it should not be performed when GO is active, but when it has been inactive for 6 months (160, 161). The goal of eye muscle surgery is to align the eyes, avoiding abnormal head posture and restoring single binocular vision in primary and reading positions; multiple operations may be required to achieve this goal.
54. Eyelid surgery may rarely be an emergency procedures in patients with exposure keratitis and corneal ulcerations, but it usually is carried out to correct eyelid malposition after medical treatment or orbital decompression. Eyelid surgery usually constitutes the last step of rehabilitation
55. furthermore, once triggered, GO might proceed independently of thyroid treatment
56. The question of whether in a patient with GO, Graves’ hyperthyroidism should be treated by non-ablative (i.e., thionamides) or ablative (i.e., radioiodine therapy, thyroidectomy, both) therapy is unanswered
TED general
1. TED is the main extrathyroidal manifestation of Graves’ disease, found in about 25% of patients at diagnosis, often mild and self-remitting.
2.TED is the main and most frequent extrathyroidal manifestation of Graves’ disease, although it may less frequently occur in patients with Hashimoto’s thyroiditis or apparently without thyroid abnormalities (so-called Euthyroid Graves’ disease)
3. There is a close temporal relationship between the onset of GO and the onset of hyperthyroidism. In approximately 85% of cases GO and hyperthyroidism occur within 18 months of each other (20), although GO may both precede (about 20% of cases) or follow (about 40% of cases) the onset of hyperthyroidism (20).
4. However, in a longitudinal cohort study, spontaneous amelioration was observed in two thirds of cases, while ocular involvement did not change with time in 20% and progressed in 14%
5. The observation that mild GO rarely progresses and often spontaneously remits was recently confirmed by a large prospective study of patients with recent onset Graves’ hyperthyroidism
6. It is worth noting that GO seems to be less frequent than in the past ... likewise, a reduction in the proportion of severe forms of GO compared to milder forms was observed (18), likely reflecting an earlier diagnosis and treatment of both hyperthyroidism and orbitopathy.
7. In summary, based on recent studies and reviews of the available literature, it can be concluded that GO is a rare disease, particularly in its severe expressions (19).
8. An important epidemiologic feature of GO is its relation with cigarette smoking (29,30). The prevalence of smokers among Graves’ women with orbitopathy is much higher than that in Graves’ women apparently without GO or in normal controls (Figure 2) (31).
9. Smoking is a predictor of Graves’ hyperthyroidism, with a hazard ratio of 1.93 in current smokers, 1.27 in ex-smokers, and 2.65 in heavy smokers (32).
10. Whether passive smoking may have the same impact as active smoking is unsettled; however, in a recent European survey of GO in childhood, ... it is likely that passive smoking rather than active smoking influenced GO occurrence
11. GO is an autoimmune inflammatory disorder related to the thyroid and triggered by the migration of autoreactive T-helper cells into the orbit,
12. The TSH receptor (TSH-R), the ultimate cause of hyperthyroidism due to Graves’ disease, is likely the shared antigen responsible for GO.
13. Both hyperthyroidism (78, 79) and hypothyroidism (80) seem to influence negatively the course of the orbitopathy.
14. TRAb are independent risk factors for GO and can help to predict severity and outcome of eye disease
15. Radioiodine therapy for Graves’ hyperthyroidism is associated with GO progression in about 15% of cases, although this effect may be transient (82-86). This effect is more frequently observed in patients who already have GO prior to radioiodine therapy, smoke, have high TRAb levels, or whose post-radioiodine hypothyroidism is not promptly corrected by L-thyroxine replacement therapy. Radioiodine-associated progression of GO can be prevented by a short course of prednisone
16. Neither thyroidectomy (typically partial) nor antithyroid drugs influence the course of the orbitopathy.
17. The above observations have important practical implications in terms of GO prevention (Table 2), because GO patients should be urged to refrain from smoking, their thyroid dysfunction (both hyper- and hypothyroidism) should be promptly corrected, and, in the case of radioiodine therapy, a short course of oral prednisone should be administered
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