Graves' Orbitopathy. Группа авторов

(DON), and as they may not be volunteered, they should be specifically elicited from all patients with progressive or otherwise symptomatic disease as detecting subtle evidence of DON is crucial. If DON is significantly asymmetrical (30%), then an afferent pupil defect will also be apparent [13].

Sight-threatening corneal ulceration is even less common than DON, but potentially devastating. It presents as an area of corneal staining, sometimes with thinning or abscess and very occasionally perforation. Corneal ulceration can only develop when normal corneal protection is lost. This occurs in those patients who not only have lagophthalmos (see above), but whose cornea remains visible when the eyelids are closed. In 90% of normal individuals the eyeball rotates upwards on eyelid closure to protect the cornea. If the inferior rectus muscle is tight as is common in GO, then this normal reflex (the Bell’s phenomenon) is lost, leaving the cornea in a more vulnerable position (Fig. 2). It is not known whether patients with extreme eyelid retraction are at greater risk of ulceration, but it is clear that sight-threatening ulceration can develop in patients without severe eyelid retraction.

Other unusual signs and symptoms of GO include superior limbic keratoconjunctivitis, inflammation of the caruncle and/or plica (see the section “How Are These Signs Assessed?” below) and episodes of globe subluxation (where the eyeball protrudes in front of the eyelids). The latter are extremely alarming for both patient and any witnesses, but fortunately affect only 0.1% of patients [14].

Hence patients with GO can show a number of clinical signs; however, it is relatively unusual to present with all of them. Only 5% of patients had the complete constellation of classic findings: eyelid retraction, exophthalmos, optic nerve dysfunction, extraocular muscle involvement, and hyperthyroidism [15].

Fig. 2. Eyelid closure: lagophthalmos and the Bell’s phenomenon. a Open eye. b Attempted eyelid closure with lagophthalmos, but no corneal exposure due to a good Bell’s phenomenon rotating the eyeball upwards. c Attempted eyelid closure with lagophthalmos and no Bell’s phenomenon, hence corneal ulceration.

What Signs Should Question the Diagnosis of Graves’ Orbitopathy?

Although ptosis can develop following long-standing GO, it is very rare for patients to present with ptosis early in the course of their disease. Such patients should be investigated for myasthenia gravis which is significantly more common in patients with autoimmune thyroid disease, as compared to the general population [16]. Similarly, divergent strabismus does occasionally occur with GO but so rarely that the diagnosis should be questioned and further investigations are required.

Are There Racial Differences in How Graves’ Orbitopathy Manifests?

GO can affect people of all races. Genetic susceptibility to Graves’ disease varies between races [17], and there is some evidence that amongst patients with Graves’ disease, susceptibility to GO also varies between races. For example, Europeans appear more likely to develop GO than Japanese Asians [18]. There are very few data on racial differences for both prevalence and presentation of GO, and the influence of important confounding factors such as smoking needs to be considered.

There is known to be significant variation in normal exophthalmometry values between races [19], with Chinese Asians showing significantly lower values than Caucasians [20], while Black people have relatively shallow orbits and show higher values. Hence exophthalmos should be assessed in relation to the normal range for the patient’s race and gender.

Is the Presentation of Graves’ Orbitopathy Different in Older Compared to Younger Patients?

There are some important differences in the presentation of GO at different ages and a tendency for overall severity to increase with age, regardless of gender [21].

Children and teenagers with Graves’ disease appear as likely as adults to develop GO, particularly in countries where teenagers are more likely to smoke [see the chapter by Bartalena, this vol., pp. 304–305; 22, 23]. However, unlike adults, they rarely develop severe disease, and the majority will require no specific treatment [24, 25]. They commonly show a degree of eyelid retraction and mild exophthalmos but rarely show muscle restriction, corneal ulceration, or optic neuropathy.

By contrast, some data suggest that patients over 50 years of age are more likely to have impaired motility than those under 50 (32 vs. 12%, respectively) with greater limitation in upgaze [5] while others show no such difference [21]. However studies consistently show a significantly higher risk of optic neuropathy with age [5, 26–28]. This may relate at least partly to a higher prevalence of concomitant vascular disease in older patients.

      Older patients are also more likely to have unilateral or very asymmetrical disease and are more likely to be euthyroid or hypothyroid at the time of presentation [5].

Why Can the Clinical Presentation of Graves’ Orbitopathy Be So Variable?

      It is not fully understood why some patients develop one pattern of tissue involvement while others show a different pattern. However some differences are likely to be due to anatomical variation: the secondary sequelae of GO relate to the interaction between the degree and speed of onset of the inflammation and the anatomical constraints of the orbit, which are at least in part racially determined. It is clear that there is premorbid variation in the relative position of the globe within the orbit and in the laxity of the anterior orbital septum (AOS)(see the section “Can You Give Me a Short Mechanistic Explanation for All These Clinical Manifestations?”).

Extraocular muscles tend to be asymmetrically involved. While most patients show some muscle involvement on imaging, up to 10% of patients show orbital fat expansion with apparently normal muscle dimensions. The latter can still lead to exophthalmos; however, restriction of eye movements is uncommon and when