stimulated by patient IgG, several cytokines, and autologouslymphocytes.Stimulationbyautologouslymphocytes is antigen-dependent, as direct cell−cell contact, MHC class II, and CD40–CD154 signaling are necessary [3]. In

16 addition, orbital fibroblasts may di erentiate to preadipocytes, which are accompanied by an increase in TSHR expression [4]. Thus, the shared candidate autoantigen between thyroid and orbita is the TSHR.

Clinically, high serum levels of TSHR antibodies (TRAb) are associated with higher prevalence and increased severity of GO. However, presence of TRAb alone does not cause the complete symptom complex. Neonates of mothers with TRAb positive GD usually develop hyperthyroidism, which gradually dwindles as antibodies are cleared from the child’s body, yet only few develop eye signs (mainly proptosis). Immunization of mice against the TSHR does generate TRAb and hyperthyroidism but no associated orbital inflammation [5]. Thus, factors other than the presence of TRAb are probably involved in the development of GD. In GD, there is a strong genetic component [see Chap. 16.5.2] involving immunoregulatory and thyroid-specific genes [6].

In most patients, there is a close temporal relationship between the onset of hyperthyroidism and orbitopathy. Orbitopathy usually manifests within 6 months before or after the first clinical signs of hyperthyroidism. MRI images of patients who su er from hyperthyroidism but not from clinically overt orbitopathy reveal orbital manifestation in more than two-thirds of those patients [7]. The development of GO is a marker for a more severe course of GD and associated with significantly lower remission rates of hyperthyroidism [8]. However, GO can also occur many years after the onset of thyroid disease or − in rare cases − long before or even without overt thyroid disease [9]. In 75% of euthyroid GO patients, thyroid-specific antibodies can be detected as indicators of associated thyroid disease [10].About half of those patients will develop thyroid dysfunction within the following 18 months [11].

16.1.2Graves Orbitopathy−Clinical Signs

Graves Orbitopathy is typically characterized by the following clinical characteristics (Fig. 16.1) [12, 13]:

■Most frequent sign (in 90–98% of patients): upper lid retraction, often with lateral flare and lid lag on vertical downward pursuit, lagophthalmos (due to fibrosis of the levator palpebrae muscle)

■Other common signs: soft tissue signs, e.g., periorbital swelling and redness, conjunctival swelling and injection, prominent glabellar rhytids (due to inflammation)

■Proptosis (exophthalmos) with possible concomitant lower lid retraction (mainly due to increased adipogenesis, but also due to enlargement of extraocular muscles and inflammatory swelling)

■Ocular surface lesions (due to lagophthalmos, increased lid width, impaired Bell’s phenomenon, and reduced tear secretion and deteriorated composition)

■Restriction of ocular excursions – most often upgaze and abduction (due to fibrosis of inferior and medial rectus muscles)

■In rare cases (about 5%), dysthyroid optic neuropathy (DON) (due to apical crowding)

16.1.2.1Clinical Changes Result in Typical Symptoms

■Change of facial appearance

■Symptoms related to inflammation: painful, oppressive feeling on or behind the globe, pain of attempted up-, lateral, or downgaze

■Symptoms related to ocular surface irritation: gritty sensation, light sensitivity, excess tearing, and reduced visual acuity

■Symptoms related to restricted ocular motility: diplopia, abnormal head positure

■Symptoms related to DON: reduced visual acuity, restricted visual field, and desaturated color perception

16.1.3Clinical Examination of GO

Determining the phase of GO at each clinical assessment [14] is fundamental to the establishment of an appropriate management plan (Fig. 16.2). Immunomodulatory therapies can only be e ective in the presence of active inflammation. Certain surgical treatments, on the other hand, (orbital, lid, or strabism surgery) should only be performed when GO has been constantly inactive for at least 6 months.

16.1.3.1Signs of Activity

The active phase of the disease is the period when the patient is most likely to be symptomatic: gaze evoked or spontaneous grittiness, light sensitivity, and excessive orbital aching – gaze evoked or spontaneous. Patients notice change of severity over the previous 3 months. Classical signs of inflammation are used as surrogate markers to evaluate the degree of orbital inflammation:

■Eyelid redness

■Conjunctival injection

■Chemosis (conjunctival edema)

■Eyelid swelling

■Inflammation of caruncle or plica

All features of soft tissue inflammation can be assessed by comparison with standard patient photographs available at www.eugogo.eu. Studies show that reproducibility of patient assessment can be improved by the use of this atlas and careful methodology (interobserver agreement − 86%). Photographic documentation is a reliable method for assessing soft tissue signs for follow-up. Signs of activity are summarized in the clinical activity score (CAS) (maximal seven points at the first visit and maximal ten points at follow-up) (Table 16.1) [16]. Using a cut-o of at least four (first visit three), the positive predictive value

was 80% in estimating the response to immunomodulation. Patients with disease duration of more than 18 months are less likely to respond to immunomodulation. A-mode ultrasound, T2 weighted or STIR sequence MRI images, and serum or urine levels of a number of inflammatory markers including IL-6, and urine GAG excretion provide only little additional benefit in predicting the response to anti-inflammatory therapy [17].

16.1.3.2Assessing Severity of GO

The following features are quantified to assess severity:

■Lid fissure width (distance between the lid margins in mm with the patient in primary position; sitting, relaxed, with distant fixation)

■Swelling of the eyelids (absent/moderate/severe)

■Redness of the eyelids (absent/present)

■Conjunctival injection (absent/present)

■Conjunctival chemosis (absent/present)

■Inflammation of the caruncle or plica (absent, present)

■Exophthalmos (measured in mm using the same Hertel exophthalmometer and same intercanthal distance for an individual patient)

■Subjective diplopia score (0 no diplopia; 1 intermittent, i.e., diplopia in primary position of gaze, when tired or when first awakening; 2 inconstant, i.e., diplopia at extremes of gaze; 3 constant, i.e., continuous diplopia in primary or reading position)

■Eye muscle involvement (duction in degrees)

■Corneal involvement (absent/punctate lesions/corneal ulcer)

■Dysthyroid optic neuropathy (DON) (best-corrected visual acuity, color (de-) saturation, optic disk, relative a erent pupillary defect (absent/present), visual fields, visually evoked potentials)

Examination of lid fissure width should be performed with the head in a stationary position and under fixation.

If vertical strabism is present, the contralateral eye should be occluded. To evaluate upper and lower lid retraction, eyelid position is measured in relation to the respective limbus.

Proptosis is usually measured with an exophthalmometer. Numerous di erent makes are available with di erent scales, so for each patient the same exophthalmometer with identical intercanthal distance should always be used for follow-up. Proptosis is defined as a reading 2 mm greater than the upper normal limit for that patient’s age, gender, and “race.” More important, however, is the measured change during follow-up.

There are numerous ways of assessing extraocular muscles. Subjective diplopia scores are simple but only of limited help, since significant changes in limitation of motility may go unnoticed, when bilateral symmetrical reduction of upgaze results in no noticeable double vision. The measurement of monocular excursions is a more exact way to assess restricted excursions of each eye separately. Excursions are best measured using a bowl or arc perimeter, but so-called “Kestenbaum glasses” or the position of light reflexes may be used as well. Normal

Table 16.1. Clinical activity score (CAS), maximal 7 points at the first visit and maximal 10 points at follow-up, active disease CAS ≥4 (three first visits)

Clinical activity score CAS (one point is given for each feature)

very large muscles in the orbital apex, fat herniation through the superior orbital fissure, and tense ballottement of the globe and venous stasis. DON is insidious as its onset is rarely obvious and visual acuity is long preserved. Color vision disturbances are present in most patients. Only 30–40% of the patients present with swelling of the optic disc. Visual field defects are most commonly paracentral or inferior. VEP amplitudes are reduced and latency periods can be delayed [14].

Severity can be scored using the NOSPECS classification, which provides in its slightly modified version a maximal score of 14 (Table 16.3) for patients with all manifestations of GO in its most active stage [19].

16.1.3.3Imaging

Orbital imaging can be necessary for di erential diagnosis as well as, in special situations, to facilitate treatment decisions.If the patient presents with asymmetrical symptoms (usually unilateral proptosis), inflammatory orbital disease of nonthyroidal etiology or orbital tumors have to be ruled out. Orbital imaging is necessary for all clinical treatment decisions in Dysthyroid optic neuropathy. Signal intensity in T2-weighted MRI scans corresponds to inflammatory edema and can be used to ease treatment decisions in di cult clinical situations. Orbital ultrasound is only informative if performed and evaluated by experienced clinicians [20].

values are given in Table 16.2. The prism cover test (separate measurement of the squint angles in primary position for far and near distances) and the field of binocular single vision are used to fit corrective prisms and to plan squint surgery.

Of outstanding importance is the evaluation of the corneal surface. This requires slit lamp examination to detect punctate fluoresceine staining or ulceration; the latter constitutes an ophthalmologic emergency.

There is no single test that proves DON. DON occurs bilateral in 70% of the patients. Anatomical indicators are

Table 16.2. Normal values for monocular excursions (after Mourits et al. [18])

16.1.4Classification of GO

Members of EUGOGO recommend to classify patients according to activity (active disease CAS ≥ 4, inactive disease CAS < 4) and according to severity to manage patients with GO [21].

Severity classification:

1.Sight-threatening GO: Patients with dysthyroid optic neuropathy (DON) or corneal breakdown. This category warrants immediate intervention.

2.Moderate-to-severe GO: Patients without sight-threat- ening GO whose eye disease has su cient impact on daily life to justify the risks of immunosuppression (if active) or surgical intervention (if inactive). Patients with moderate-to-severe GO usually present with 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, intermittent, or constant diplopia.