British Journal of Radiology 75 (2002),514-517 © 2002 The British Institute of Radiology
Can contrast enhanced MRI predict the response of Graves' ophthalmopathy to orbital radiotherapy?
M Ott, MD1,
N Breiter, MD2,
C F Albrecht, MD1,
O Pradier, MD1,
C F Hess, MD, PhD1 and
H Schmidberger, MD1
Departments of 1 Radiotherapy and 2 Neuroradiology, University Hospital, 37075 Göttingen, Germany
Correspondence: Dr Marcel Ott, Universitätsklinik, Abt. Strahlentherapie, Robert-Koch-Str. 40, 37075 Göttingen, Germany
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Abstract
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The purpose of this study was to try to determine by means of contrast-enhanced MRI, a subset of patients with Graves' ophthalmopathy who will not respond to orbital radiotherapy. 54 patients with Graves' ophthalmopathy were treated with orbital radiotherapy (10 x 2 Gy) and symptom relief was recorded. MRI examinations prior to radiotherapy were retrospectively evaluated for enlargement, contrast enhancement and fibrotic changes in extraocular muscles and surrounding soft tissue. Imaging data were correlated with clinical features and response. Symptom relief was observed in 61% of patients but this could not be predicted by any of the MRI signs investigated. However, there is a trend for a better treatment reponse in patients who show contrast enhancement of extraocular muscles prior to orbital radiotherapy (p=0.08). MRI could not adequately predict the efficacy of orbital radiotherapy in this group of patients. Clinical assessment of disease activity is still the most reliable method.
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Introduction
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Orbital radiotherapy (ORT) is a standard treatment for patients with moderately advanced Graves' ophthalmopathy (GO) leading to symptom improvement in 60–80% of patients [1–4]. However, some patients report no change or sometimes worsening of symptoms following ORT. Side-effects of ORT are rare but the calculated statistical risk of carcinogenesis [5] and reports of retinopathy [6] following ORT have indicated the need for a better selection of patients that may benefit from ORT.
MRI of the orbits can show enlargement of extraocular muscles (EOM), as well as inflammatory signs, using contrast media. Moreover, fibrotic changes in EOM, which are said to be responsible for the radioresistance of some GO patients, can also be detected. Thus, the objective radiological signs of disease activity may permit the prediction of clinical response.
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Materials and methods
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54 patients (median age 47 years, range 17–74 years) with GO grade III–IV according to the Werner score [7], treated with ORT at our institution between 1996 and 2000, were reviewed retrospectively. Another 21 patients treated during the same time period were not included, because either no MR scans were available (18 patients) or the available images were considered technically inadequate (3 patients). In 2 of 54 patients, MRI was performed without contrast media. Patient characteristics according to potential prognostic factors are listed in Table 1
. ORT consisted of 10 x 2 Gy in 2 weeks, delivered by individually planned (usually 5 cm x 5 cm) portals using 6 MV LINAC photons. A half-beam technique was employed to protect the lenses. The response to ORT was measured by the subjective improvement of symptoms. Patients were first examined 2 weeks post-treatment, and subsequent examinations were performed from 2 months to 8 months post-treatment where there were changes or worsening symptoms.
MRI was usually performed prior to ORT, with T1 and T2 weighted images in transverse and coronal planes and a section thickness of 3–5 mm, using either fat saturation or fat suppression sequences. Contrast enhanced T1 images were obtained following administration of 8 mg kg-1 gadolinium iv.
MR scans were independently assessed by an experienced radiologist (NB) for visible enlargement of EOM and contrast enhancement of EOM (Figure 1) or surrounding orbital tissue (which was assumed to be an inflammatory infiltration (Figure 2a)). In addition, inhomogeneous areas within enhanced EOM in T1 images or within a marked T2 signal were judged to be fibrotic changes (Figure 3).
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Figure 1. T1 weighted fat saturated frontal image showing enlargement of extraocular muscles, especially the superior and inferior rectus muscles of both sides with marked contrast enhancement.
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Figure 2. T1 weighted fat saturated frontal images showing additional contrast enhacement of adjacent orbital tissue surrounding the extraocular muscles prior to orbital radiotherapy (ORT) (a), which is thought to be a sign of acute inflammation. A marked decrease in contrast enhancement and muscle size was found 3 months following ORT (b), which was accompanied by clinical improvement.
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Figure 3. T1 weighted fat saturated axial image showing an area of inhomogeneous contrast enhancement of an enlarged medial rectus muscle (arrow) which is judged to be fibrosis in a chronically inflamed muscle.
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The results of response to ORT and of image assessment were analysed using the 
2 test for non-parametric estimations, a level of p<0.05 being regarded as significant.
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Results
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Of 54 patients treated, 33 (61%) reported an improvement of GO symptoms following ORT. The majority of these patients experienced a decrease in soft tissue symptoms. Analysis of pre-treatment MR images revealed an enlargement of EOM in 49 (91%) of 54 patients. Contrast enhancement of EOM was detected in 43 (83%) of 52 patients and of surrounding orbital tissue in 36 (69%) of 52 patients. Changes in the signal intensity in EOM corresponding to fibrosis were seen in 18 (33%) of 54 patients. Of 43 patients who showed an enhancement of EOM, 28 (65%) also showed an improvement of symptoms following ORT. In contrast, only 3 (9%) of 33 patients with a clinical response showed no enhancement of EOM.
Statistical analysis showed that the correlation between the radiological signs described above and the clinical response to ORT did not reach significance but there was a trend towards better response to ORT in patients with contrast enhancement of EOM prior to treatment, with a p-value of 0.08. Moreover, none of the clinical prognostic factors tested correlated significantly with the clinical reponse in our patient group. A summary of response data and resulting p-values is given in Table 2.
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Discussion
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Retrospective studies have found that a variety of prognostic factors, including male gender, smoking, thyroid status and severity of thyrotoxic symptoms (according to the Werner score), correlated with the severity of symptoms of GO and poorer clinical outcome following ORT [1, 4, 8, 9]. The addition of steroids to ORT has been shown to improve outcome [10] but the use of steroids in GO is not generally favoured owing to a greater frequency and severity of side-effects [10, 11]. None of the above prognostic factors has proved to be correlated significantly with treatment response in our patient group, despite an overall response rate of 61%, which is comparable to results published in the literature. A randomized trial comparing ORT and sham irradiation showed a significantly better outcome for the group receiving ORT only in the improvement in diplopia. Therefore, responses to ORT in patients with grade II–III ophthalmopathy were compared with responses in patients with grade IV ophthalmopathy, and no significant difference in response to ORT was found. Hence, our results indicate that the recognized prognostic factors do not predict the clinical outcome of ORT.
The cause of GO is an autoimmune process which is maintained by a T-cell infiltration of orbital tissues, leading to oedema of EOM and connective tissues [12]. This lymphocytic infiltrate is the main target for irradiation. During the natural course of GO, acute infiltration can turn into hypertrophy and fibrosis of orbital fat and muscles, which is then thought to be unable to respond to steroids or irradiation [13].
Clinical activity scores take into account features such as pain, visible swelling and redness. However, about 30% of patients with high disease activity scores do not respond to treatment [14]. In an attempt to predict response, measurements of EOM thickness on CT scans were used in a number of studies during the 1980s, and more recently MRI has been used for measurements. Both CT and MRI scans showed a significant enlargement of EOM in almost all GO patients [15–17] that was correlated with disease activity but not with response to anti-inflammatory treatment using steroids or ORT [18, 19]. Observations in this study were similar; there was no significant difference in response in 91% of patients with EOM swelling compared with the normal sized EOM. However, assessment of EOM enlargement in our study was only subjective, without measuring the size of the muscle. Oedema in EOM, a sign of disease activity, was demonstrated in about 40–90% of GO patients using T2 weighted fat saturated sequences [20, 21] while fibrotic changes were found in only 10% [20]. This is a much lower figure than in our study (33%), probably owing to the less well defined criteria for fibrosis.
Additional T2 relaxation time measurements showed a good correlation with clinical response to ORT in one study of 27 patients [22]. The same investigators used T2 relaxation time measurements to evaluate the outcome of ORT after either 10 GY or 24 Gy. They found that patients who received the higher radiation dose showed a significant decrease in T2 relaxation times and a better clinical reponse [23]. Just et al [24] found a similar decrease in T2 times in the EOM after ORT. However, the clinical response did not correspond with high T2 times before treatment, thus making it difficult to predict reponse. Although there was correlation between T2 relaxation times and disease activity, this is not widely used as it is diffult to perform and time consuming.
Contrast enhanced MRI using gadolinium is easy to perform and permits the detection of inflamed EOM which were found in 83% of our patients. Again, only a subjective assessment of contrast enhancement was performed. This is the first study in which the predictive value of contrast enhaced MRI for the response of GO to ORT has been analysed and future studies should use measurements of the contrast enhancement ratio to provide a basis for the objective comparison of clinical features and imaging findings. Although a statistically significant correlation between these could not be found in our study, there is a promising trend towards better treatment results in patients with contrast enhancement of EOM (p=0.08), which might reach significance with a larger numbers of patients.
However, contrast enhanced MRI, like other imaging modalities, has so far failed to predict treatment response to ORT and treatment decisions have still to be based on clinical features.
Received for publication August 22, 2001.
Accepted for publication December 20, 2001.
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Abstract
Introduction
