Keywords

FormalPara Learning Objectives

  • There is an abundance of symptoms and signs in Graves’ orbitopathy. Nevertheless (or because of this), the diagnosis can be challenging

  • In order to start the right treatment, the patient must be classified in terms of disease severity and activity

  • The orbitopathy has a huge impact on the life of patients with Graves’ orbitopathy. Generally, the changed appearance is perhaps the most significant of all aspects of Graves’ orbitopathy, although not every patient would easily admit that

Symptoms and Signs

Undoubtedly, exophthalmos is the best-known sign of patients with Graves’ orbitopathy (GO). It occurs in 60% of patients diagnosed with GO. Exophthalmos means an axial globe position above the limit of normal (Chap. 7). However, upper eyelid retraction is more common and is seen in at least 90% of the patients [1,2,3]. The combination of eyelid retraction and exophthalmos is responsible for the change in externality. The resulting ‘startling appearance’ is the source of social disregard and reduced self-acceptance. Patients avoid being photographed and feel they do not look what they are or were.

Frank upper lid retraction may be preceded by scleral show in downgaze, called von Graefe’s sign: when looking downward, the upper lid is not exactly following the eyeball and the white sclera above the corneal limbus (or iris) becomes visible.

Due to the increased surface of the eye exposed to the outside world, the eye starts to feel gritty, may start tearing spontaneously, while bright light is less tolerated (photophobia). The patient tries to compensate for these inconveniences by squeezing with the eyelids, which in turn leads to frowns on the forehead and negatively contributes to the changed appearance (Figs. 15.1 and 15.2). Apart from upper lid retraction, there may be lower lid retraction and lagophthalmos (the eyes cannot be closed completely), which contributes to the evaporation of the tear film, eventually resulting in breakdown of the corneal epithelium. If not treated adequately and in time, a corneal ulcer may develop that can cause permanent blindness.

Fig. 15.1
A photo of the woman's face exhibits the infected eye with abnormally high-positioned eyelids.

Historic photograph of a woman with upper lid retraction and exophthalmos. Note the frowns on her forehead (taken from Wikipedia—public domain)

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Fig. 15.2
A photo of the man's face exhibits the infected eye with abnormally raised margins of the upper and lower eyelids. It indicates the swelling of the conjunctiva and the area around the eyelids.

Male patient with severe and vision-threatening GO: extreme proptosis, eyelid retraction and swelling. He reported a markedly decreased quality of life

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In the next phase, the eyelids become swollen, either due to edema or to an increase of fat tissue. The conjunctiva also becomes swollen (chemosis), and epibulbar blood vessels dilate, causing a reddish appearance. Around 40% of GO-patients show motility impairment. Because the inferior rectus muscle is most often involved, an elevation impairment is most frequently seen. When the inferior rectus of both eyes is equally involved, the patient will compensate for the inability to elevate her/his eyes by keeping the head back (torticollis). This head posture may (wrongly) be perceived as an arrogant attitude. When the inferior recti muscles are unequally affected, double vision becomes inevitable as long as both eyes have good vision. Apart from vertical impairment of eye movements, motility reduction can occur in any direction of gaze.

In the most severe presentation of GO, called Dysthyroid Optic Neuropathy (DON) [4], a number of symptoms become evident that are related to compression or stretching of the optic nerve due to increased soft tissue volumes in the orbit. These are reduced color vision (especially in the blue/yellow axis), reduced visual acuity, reduced visual fields and—in case of predominantly unilateral GO—a Relative Afferent Pupil Defect (RAPD; the pupil at the most affected side becomes larger rather than smaller when illuminating each eye alternately). Ophthalmoscopy shows a swollen optic nerve head and choroidal folds.

The most distressing sign of GO is globe luxation: the globe becomes positioned anterior to the eyelids. This can happen with sagging eyelids. Gentle pressure puts the eye back in place.

Typical of GO is the diversity of clinical signs and symptoms. Typical also is the asymmetry. GO is the most common cause of bilateral, but also of unilateral, exophthalmos. But even in bilateral GO, the presentation of the two sides may differ considerably.

Diagnosis, Imaging and Differential Diagnosis

Despite the multitude of symptoms and signs, a diagnosis of GO remains difficult. In 70% of patients referred to a specialized center for Graves’ disease, the question was: ‘Is this GO?’ In such a center, an ophthalmologist together with an endocrinologist were able to rule out GO in about 10%, and to confirm GO in >80%. Diagnosis of GO is based on the combination of the following items:

  1. 1.

    Upper lid retraction

  2. 2.

    Exophthalmos

  3. 3.

    Eye movement reduction, especially elevation restriction

  4. 4.

    (Family) history of Graves’ disease

  5. 5.

    Enlarged extraocular muscle(s) on CT scan or MRI scan

  6. 6.

    Presence of auto-antibodies: TSH-receptor-binding immunoglobulins (TBII), thyroid peroxidase antibodies (anti-TPO)

Eyelid swelling is deliberately not included in this list, because it is a non-specific sign which can also be seen in healthy elderly people and is often seen in smokers. Strict criteria for a definition of eyelid swelling do not exist, and therefore, the prevalence of eyelid swelling is unknown. However, it is important to consider GO in patients with non-understood eyelid swelling, even when other manifestations of GO are lacking. Blepharoplasty to correct eyelid swelling in patients with a beginning GO easily results in eyelid retraction and it will be difficult for the surgeon to explain afterwards that eyelid retraction would have occurred anyway (e.g., without a previous operation).

As described above, the following items are paramount in the diagnosis of GO

  1. 1.

    Upper eyelid retraction can be congenital or the result of a contralateral blepharoptosis. It can also be caused by eyelid fibrosis secondary to trauma or surgery. It is sometimes seen in patients having undergone a (too enthusiastically performed) blepharoplasty.

  2. 2.

    Exophthalmos is seen in many conditions, such as shown in Chap. 7. The combination of upper eyelid retraction and exophthalmos is extremely suggestive for GO. In contrast, the combination of blepharoptosis and exophthalmos is highly suggestive for other diseases than GO.

  3. 3.

    Acquired motility impairment with or without diplopia is also very suggestive for GO. In the early stages, patients typically complain about double vision in the early morning or when tired. Another cause of acquired double vision is a palsy of the fourth cranial nerve (trochlear nerve), seen after trauma, in patients with diabetes mellitus or otherwise healthy, though elderly people. In contrast to patients with GO, in order to compensate for their double vision, they tilt their head down.

  4. 4.

    GO is assumed to originate from genetic mutations that predispose to disease and interact with environmental factors, such as infections, through epigenetic modification [5]. Whether true or not, GO is seen in families with kinswoman that have or have had GD far more frequently than expected by coincidence. Obviously, the presence of GD in relatives, only supports, but does not prove GO.

  5. 5.

    As discussed above, extraocular muscle enlargement is an early phenomenon and occurs in up to 70% of the patients [6]. The inferior and medial recti are most frequently involved. One or more muscles may be enlarged, but it is uncommon for the lateral rectus muscle to be solely enlarged (in contrast to the inferior and medial recti). In contrast to myositis, in which the lateral rectus muscle is often affected as the only extraocular muscle, the tendons of the muscles in GO are not thickened. Enlargement of the tendons together with evident pain is very suggestive for myositis or other forms of idiopathic orbital inflammation (Chap. 5). Swelling of the extraocular muscles can also be seen in caroticocavernous fistulas. The muscles are swollen due to congestion.

  6. 6.

    Both CT and MRI scans are helpful in making a diagnosis of GO. CT scans have the advantage of a clear visualization of the orbital bones, which is useful in preparing for orbital decompression. The disadvantage is the irradiation burden. MRI scans have no radiation burden at all and can help to distinguish between active and burnt-out GO (see next session). Both CT scans and MRI scans show enlargement of the extraocular muscles, apical crowding and stretching of the optic nerve and tenting of the posterior sclera, when present. Moreover, these scans also help to rule out other diseases than GO. TBII and/or anti-TPO serum levels are elevated in more than 95% of patients with GO [7].

Severity

In each patient with GO, the disease severity grade and the activity stage have to be assessed. For grading the disease severity, the Werner’s NOSPECS classification has been used [8], but the EUGOGO classification is easier and probably more relevant [3]. Three classes of severity are distinguished:

  1. 1.

    Mild GO: There are only mild symptoms and signs that are not or hardly interfering with daily life activities. These could be eyelid retraction, mild proptosis, mild motility impairment without significant diplopia and/or mild corneal involvement (stippling of the corneal epithelium). Approximately, 60% of all patients with GO have this mild form. Treatment consists of lubricants and dark glasses. Smoking must be discouraged. Otherwise, a wait-and-see policy is justified. If there are signs of disease activity, selenium can be considered [9]. When the situation is stable for 6 months, corrective surgery can be started.

  2. 2.

    Moderate GO: There is significant eyelid swelling and/or proptosis. Evident restriction of eye movements causes torticollis and/or diplopia. Daily life activities are seriously affected. Around 35% of patients seen at tertiary referral centers suffer from this form. Especially in this group, assessment of disease activity is of the utmost importance. Patients with active GO are initially treated with immunosuppressive therapy. When the disease has become or is stable, rehabilitating surgical steps can be undertaken.

  3. 3.

    Severe or vision-threatening GO: Also called Dysthyroid Optic Neuropathy (DON) [5]. Due to extreme swelling of the orbital soft tissues in combination with a tight orbital septum and subsequent raised intra-orbital pressure [10], the optic nerve becomes stretched or compressed, eventually leading to blindness. This is an exceptional form, which only occurs in about 5% of patients. Interestingly, the amount of proptosis is usually not excessive. A tight orbital septum is believed to prevent auto-decompression, thus causing less exophthalmos and DON [11]. Patients with DON always have active GO. Immediately, immunosuppressive treatment should be started. When there is no or an insufficient response, orbital decompression should be performed. Even in patients with longstanding blindness due to DON, orbital decompression may result in the return of vision. A corneal ulcer can also lead to vision loss. In countries with good and accessible health care, it is rarely seen. Finally, globe luxation is also vision-threatening and needs immediate correction.

Activity

Also, the disease activity has to be scored. As discussed above, the initial phase of Rundle’s curve is associated with inflammation and worsening of signs and symptoms.

Immunosuppressive treatments, such as glucocorticosteroids or orbital irradiation, are thought to be effective only in the active stage of the disease. On the other hand, certain surgical treatments, such strabismus surgery, should only be undertaken when the disease is quiet and no changes have been observed for at least 3–6 months. Thus, it is important to distinguish patients who have active and patients who have burnt-out GO. Patients with moderate or severe as well as active GO should be treated with immunosuppressive therapy, whereas patients with burnt-out GO can be scheduled for surgical intervention(s).

To assess the activity of GO, the Clinical Activity Score (CAS) has been developed [12]. The CAS (Table 15.1) is based on the classic signs of inflammation, e.g., rubor (redness), dolor (pain), tumor (swelling) and function laesa (impaired function). The fifth classic sign of Celsius has not been included, because the CAS is a clinical score, that—for the sake of convenience—should be applied without special instruments such as a heat detector (Figs. 15.3 and 15.4).

Table 15.1 The Clinical Activity Score (CAS) for GO by Mourits et al. (1989) [12]
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Fig. 15.3
A photo of the woman's face exhibits the raised margins of the infected eye with inflammation and swelling of the conjunctiva.

A 40-year-old female with active GO: pain, eyelid swelling, redness conjunctiva and chemosis; CAS = 4

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Fig. 15.4
A photo of the woman's face exhibits abnormally high-positioned upper eyelids with swelling around them.

A 44-year-old female with remaining upper lid retraction and swelling, and unchanged convergent strabismus, in burnt-out GO, CAS = 1

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For each of the signs present, one point is given. The sum of these points defines the activity score. Items 1–7 can be scored after one visit; items 8–10 require at least two subsequent visits with an interval of at least 1 month.

Our initial study showed that patients with a CAS of three or more out of 10 responded well to immunosuppressive treatment, while those with less than three points were likely not to respond [12]. The CAS has been criticized for several reasons. Firstly, all features are given equal weighting, and it is not clear whether this is appropriate. Secondly, the first seven items are subjective. Thirdly, the scoring is binary. Some improvement is not sufficient to alter the score of each item. Dickinson and Perros, therefore, developed for the EUGOGO a photographic atlas of graded inflammatory signs, which is available at www.eugogo.org, to overcome some of these drawbacks [13]. In spite of its disadvantages, the CAS has become quite popular and a fixed item of randomized clinical trials [14,15,16]. With some effort, observers reached agreement in 86% of cases [17]. In a subsequent study, we showed that, using a cut-off point of 4 on a scale of 10, the positive predictive value of the CAS was 80%, the negative predictive value 64%, the sensitivity 55% and the specificity 86% [18]. It should be realized that response to prednisone or irradiation as a quality measure of the CAS is a derivative and does not take into account that prednisone is ineffective in some individuals. We found that intravenously administered prednisone stabilizes active GO in 85% and reduces the severity of GO in 38% of the treated patients. It appears that some patients do not respond to prednisone at all, and this becomes clear already after several weeks [19, 20].

The intrinsic value of the CAS has been further established by its relationship with TBII serum levels, ultrasonography and octreotide uptake on octreotide scintigraphy, all of which are considered parameters of disease activity [21,22,23]. Over the years, there has been a tendency to use the first seven items of the CAS only, which has the advantage that a score can be assessed on the same day during the first visit. The 7-item CAS, however, has never been evaluated for its predicting value.

Impact and Quality of Life

The changed appearance, complaints of painful eyes, double vision and blurred vision have a major impact on the patient with GO. Parties are avoided, driving becomes difficult or impossible; the hot flush caused by the hyperthyroidism can easily lead to arguments. Not infrequently, patients with a severe form of GO often lose both their partner and their job. The long duration of more serious forms of GO (up to 5 years) plays a role in this. Patients with GO score their situation worse than patients with type-I diabetes mellitus do.

Gerding et al. demonstrated that the quality of life in patients with GO is markedly decreased [24]. Forty percent of our patients reports limitations of daily life activities, such as driving a car or leisure activities, 80% mentions reduced self-confidence and 44% complains about some kind of social isolation.

Terwee et al. developed a disease-specific quality-of-life questionnaire for patients with GO, the so-called GO-QOL, which is very helpful in studies to perceive the disease from the patient’s point of view [25].