240 Wiersinga

Table 1 Methods to Assess Disease Activity in Graves’ Ophthalmopathy

METHODS TO ASSESS DISEASE ACTIVITY IN

GRAVES’ OPHTHALMOPATHY

There are several ways in which the activity of GO can be assessed, as listed in Table 1. The time-honored method has been to observe the patient; if the eye changes remain stable over a period of 6–8 months, the eye disease is most probably inactive and rehabilitative surgery can be done. If not, the eye disease is probably still active, and rehabilitative surgery is then better postponed because improvement of eye changes obtained from surgery may be lost after a few months due to ongoing inflammatory reactions in the orbital tissues.

CLINICAL ACTIVITY SCORE

The clinical activity score (CAS) was designed by Mourits et al. (9) based on the classical signs of inflammation, pain, redness, swelling, and impaired function. The score assigns one point each for the presence of the following items: painful oppressive feeling on or behind the globe during the last 4 weeks; pain on attempted up-, side or downgaze; redness of the eyelid(s); diffuse redness of the conjunctiva covering at least one quadrant; swelling of the eyelid(s); chemosis; swollen caruncle; increase in proptosis of 2 mm or more during a period of 1–3 months; decrease of eye movements in any duration equal to or greater than 5 during a period of 1–3 months, and decrease of visual acuity of 1 or more lines on the Snellen

chart using a pinhole during a period of 1–3 months. The maximal score is thus 10. Patients with a high CAS are supposedly more likely to respond to immunosuppression and indeed as tested in a prospective manner, a CAS of 4 or higher had a positive predictive value (þve PV) of 80% in this respect, whereas a CAS of less than 4 had a negative predictive value (–ve PV) of 64% (10). The disadvantage of the CAS is that it is still largely subjective in nature, with consequently a large interobserver variation. To improve observer agreement, a recently published color atlas depicting grading of the various signs can be of much help (11). The advantage of the CAS is that it is inexpensive and can be done instantaneously in a few minutes. Omitting the last three items of the CAS (i.e., the changes in proptosis, eye muscle motility, and visual acuity over the last few months, thereby decreasing the maximal score to 7) is also useful and has been recommended by a committee of the four international thyroid associations (12).

ORBITAL ECHOGRAPHY

Ultrasound is a noninvasive method to visualize orbital contents and has been used to measure the thickness of eye muscles. It can also depict the internal echogenicity of eye muscles, which is best done using two-dimensional A-mode echography. The sound beam is directed perpendicular to the axis of the rectus muscles, and reflectivity is determined at the muscle belly. The eye muscle reflectivity is calculated from Polaroid pictures by measuring the distance from the baseline to the mean of the tops of all spikes within the anterior and posterior muscle sheaths and expressed as a percentage of the initial scleral spike, which is set at 100%. Due to the orbital configuration, it is difficult to obtain a reproducible image of the inferior rectus muscles. Therefore, reflectivity is assessed only in the superior, medial, and lateral rectus muscles. The intraand interobserver coefficients of repeatability are 10.2% and 11.9%, respectively, in GO patients (13).

It was hypothesized that the internal reflectivity of the sound beam would be low in patients with active eye disease

due to muscle edema, and high and irregular in inactive eye disease due to muscle fibrosis. Indeed, pretreatment reflectivity of < 30% in the eye muscle with lowest reflectivity occurred more frequently in 28 responders than in 28 nonresponders to retrobulbar irradiation (39% vs. 7%, p ¼ 0.004) (14). Using the cut-off value of 30%, the þve PV was 85% and the ve PV 60%. No correlation was found between eye muscle reflectivity and CAS. The advantage of A-mode ultrasonography is its noninvasive nature. Disadvantages are the rather low –ve PV and that the precision of the technique is very much operatordependent. The low –ve PV might be due to the inability to reliably assess the inferior rectus muscle, which happens to be the most frequently involved eye muscle in GO clinically.

ORBITAL OCTREOSCAN

Somatostatin receptors are expressed on activated T-lymphocytes and on orbital fibroblasts, even to a greater extent in fibroblasts derived from GO patients than from controls (15). By radiolabeling the long-acting somatostatin analogue octreotide, tissues that express somatostatin receptors can be visualized. This provides the rationale for applying [111In-DTPA-D-Phe1] octreotide scintigraphy (Octreoscan ) in GO patients.

The orbital uptake of radiolabeled octreotide is specific, as peak activity in the orbit 5 hr after injection (set at 100%) decreases to 40% at 24 hr, significantly different from the decrease in blood pool radioactivity (from 100% at 5 hr to 15% at 24 hr) (16). Whereas some but not all studies report a direct relationship between orbital uptake and the severity of GO, all studies observe a higher uptake in active than in inactive eye disease (16–18). The orbital uptake is directly related to other parameters of disease activity, like the CAS (16,19) and the T2 relaxation time on magnetic resonance imaging (MRI) (20). Successful immunosuppression is associated with a fall in the orbital uptake (17,19).

There are, however, wide differences between the various studies in the administered dose of radiolabeled

octreotide, in the time interval after injection for determining the uptake, in the selection of orbital slices for quantification of orbital uptake, and in the methods of correction for background radioactivity (21). For accurate prediction, a standardization of the technique is required. In correcting for background radioactivity, we observed that uptake in the occipital area of the skull had less variability than uptake in the temporal skull area. Moreover, a substantial part of the temporal uptake is due to uptake in the parotid gland (22). Consequently, we calculate the orbital to occipital uptake ratio in fixed rectangular regions of interest, selecting the four slices with maximal orbital uptake in the transverse plane, using the pituitary gland as the anatomical reference. Eight orbital images are analyzed per patient, and the number of counts is averaged. By doing so, we observed that the orbital to occipital uptake ratio 4 hr after a mean dose of 111 MBq-radiolabeled octreotide was significantly higher in patients who subsequently responded to orbital radiotherapy than in nonresponders (22). Using a cut-off value of the uptake ratio of 1.85, the þve PV was 92% and the –ve PV 70%.

The advantage of the orbital octreoscan is that it provides a rather good prediction of outcome of immunosuppression. Limitations are, however, manifold: it is a demanding technique in terms of accuracy for prediction; expensive; has a non-negligible radiation burden (of 16 mSv at a dose of 222 MBq); nonspecific (positive scans are also seen in meningioma, lymphoma, and inflammatory disorders); and provides no imaging of orbital structures (computed tomographic or MR scans are still required). It thus remains to be seen if orbital octreotide scintigraphy will become a widely applied tool in the management of GO patients.

ORBITAL MAGNETIC RESONANCE IMAGING

Orbital MRI may discriminate between active and inactive eye disease by its ability to distinguish between edema and fibrosis; an increased water content of tissues will result in a longer T2 relaxation time. Indeed, T2 relaxation times of