Graves' Orbitopathy. Группа авторов

to 1 or several muscles. About 1 in 10 patients presents with unilateral exophthalmos of 2 mm or more [29]. Smoking is associated with more severe GO.

Fig. 3. Diagrammatic representation of secondary effects of GO. Secondary effects depend partly on the laxity of the AOS shown in red. a Normal relationships of structure within the orbit. b Gross compression of the nerve (white arrows) caused by increased orbital muscle volume unaccompanied by significant exophthalmos: therefore high intraorbital pressure. c Gross self-decompression. The optic nerve may be compromised by stretching.

Can You Give Me a Short Mechanistic Explanation for All These Clinical Manifestations?

When inflammation develops in orbital soft tissues, particularly muscle and fat, hydrophilic glycosaminoglycans are produced which promote further tissue swelling. Similar inflammation in the eyelids causes visible oedema, erythema and festoons. These are the primary effects of GO and when they affect the muscles, they commonly lead to dysfunction due to a failure of relaxation. This limits movement into the field of the ipsilateral antagonist, which, if asymmetrical, causes double vision. Unfortunately, the orbit is a tight space, which is completely surrounded by bone except anteriorly. Here, instead of bone, there is a fascial sheet extending across the top and bottom of the orbital opening and known as the anterior orbital septum (AOS). The AOS limits anterior movement of the orbital contents to a greater or lesser extent. Patients with orbital tissue swelling and a very tight AOS cannot develop significant exophthalmos, but instead will experience a marked rise in intraorbital pressure [30]. Secondary effects of GO may then ensue, with pressure on the optic nerve leading to colour impairment, altered pupil responses and loss of vision. In contrast, patients with equivalent intraorbital soft-tissue swelling but with a lax AOS will “self-decompress” to develop exophthalmos (another secondary manifestation) but less rise in intraorbital pressure. This is the reason why clinicians should be particularly alert to the risk of DON in patients with muscle restriction but without exophthalmos and is illustrated diagrammatically in Figure 3.

      Upper eyelid retraction is multifactorial [4, 9, 26] and due to a combination of increased sympathetic stimulation of Müller’s muscle, contraction of the levator muscle due to its direct involvement, and scarring between the lacrimal gland fascia and levator, which specifically gives rise to lateral flare [8]. In addition, tight restriction of the inferior rectus leads to upper eyelid retraction, regardless of upper eyelid pathology [9].

Fig. 4. The relationship between activity and severity.

      In contrast, lower eyelid retraction correlates with exophthalmos and may be better described as lower eyelid displacement, as there is no evidence that the lower lid retractors are involved in the disease process.

      All corneal signs of GO are secondary phenomena of GO. A wide palpebral aperture leads to increased tear evaporation, which, combined with poor blinking, causes superficial punctate erosions and the symptoms of surface irritation [10]. The mechanism for corneal ulceration is described above in “What Are the Other Signs and Symptoms of Graves’ Orbitopathy?” and arises from lagophthalmos and corneal exposure, due to exophthalmos, lower lid retraction, and/or poor levator function, usually accompanied by a tight inferior rectus [4].

What Do the Terms “Activity” and “Severity” Denote?

During the course of GO, the disease passes through several phases. From the onset, the first phase involves worsening symptoms and signs, often with visible evidence of inflammation, followed by a plateau phase during which no further deterioration occurs. A phase of gradual improvement follows until eventually no further change occurs, although permanent abnormalities in both function and appearance may remain. Such a pattern in the course of the disease is referred to as “Rundle’s curve” [31].

The “severity” of GO describes the degree of functional or cosmetic deficit at any stage [4, 32]. What is now apparent is that the first 3 phases represent a time during which there is thought to be inflammation, and these are known as the “active” phases of GO [4, 11, 33]. Hence “activity” refers to the presence of inflammation. In contrast, the final stage is not accompanied by further spontaneous change as any inflammation has probably resolved, and this is therefore referred to as the inactive phase of GO. Figure 4 illustrates the presumed relationship between severity and activity although it is not known whether the onset of activity significantly precedes any demonstrable clinical signs, i.e., severity.

Why Is It Important to Distinguish Activity and Severity when Evaluating Patients?

      Determining the phase of GO at each clinical assessment is fundamental to formulating an appropriate management plan. This is because immunomodulatory therapies can only be effective while there is active inflammation. On the other hand, certain surgical treatments, for example strabismus surgery, should only be undertaken when GO is inactive and there is no further chance of spontaneous change. Furthermore, sight-threatening disease occurs insidiously during active GO; therefore symptoms and signs of corneal ulceration and DON should be specifically sought during this phase [4].

What Signs and Symptoms Are Valuable for Assessing Activity?

      The active phase of GO is the period when the patient is most likely to be symptomatic, commonly presenting with grittiness, photophobia, watering, and/or orbital aching – either gaze evoked or spontaneous. Patients will often have noticed a change in the severity of other features over the previous 3 months, for example worsening double vision. As we cannot directly identify the degree of orbital inflammation, i.e., activity, the classical signs of inflammation are used as its surrogate markers. In addition, if there has been a change in severity of any feature, worsening or improvement, then this also suggests that the disease is active.

How Are These Signs Assessed?

      In